Localized Non-small Cell Lung Cancer Research Articles

KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition.

Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in tumors with KEAP1/NFE2L2 mutations, indicating that they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1-mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations. SIGNIFICANCE: This study shows that mutations in KEAP1 and NFE2L2 predict for LR after radiotherapy but not surgery in patients with NSCLC. Approximately half of all LRs are associated with these mutations and glutaminase inhibition may allow personalized radiosensitization of KEAP1/NFE2L2-mutant tumors.This article is highlighted in the In This Issue feature, p. 1775.

Video-Assisted Thoracoscopic Sleeve Lobectomy for Centrally Located Non-small Cell Lung Cancer: A Meta-analysis.

Whether video-assisted thoracoscopic surgery (VATS) sleeve lobectomy could be an alternative to traditional thoracotomy sleeve lobectomy in treating centrally located non-small cell lung cancer (NSCLC) remains unclear. Therefore, we conducted the first meta-analysis to compare the effects of VATS sleeve lobectomy with thoracotomy sleeve lobectomy. We systematically searched relevant studies from Pubmed, Embase, and Web of Science on May 12, 2020. Data for analysis included short-term outcomes (blood loss, lymph node dissected, operation time, hospital stay, complications) and long-term outcomes (3-year overall survival (OS) and progression-free survival (PFS) rates). We calculated the weighted mean differences (WMDs) for continuous data and risk ratio (RR) for pooling categorical data. We finally included 5 retrospective cohort study consisting of 436 patients. VATS sleeve lobectomy yielded significantly less blood loss (WMD = -37.83; 95% confidence intervals (CIs) = [-58.56, -17.11]; P < 0.001) than thoracotomy sleeve lobectomy and comparable total number of dissected lymph node to thoracotomy sleeve lobectomy (WMD = - 0.07; 95%CI = [-1.14, 0.99]; P = 0.89). However, VATS sleeve lobectomy consumed significantly more operation time than thoracotomy sleeve lobectomy (WMD = 49.00; 95%CI = [14.67, 83.34]; P = 0.005). VATS sleeve lobectomy yielded significantly less postoperative hospital stay time than thoracotomy sleeve lobectomy (WMD = -1.68; 95%CI = [-2.98, -0.39]; P = 0.011) and comparable postoperative complication rate to thoracotomy sleeve lobectomy (RR = 0.84; 95%CI = [0.49, 1.44]; P = 0.52). Moreover, VATS sleeve lobectomy yielded comparable 3-year OS (RR = 1.08; 95%CI = [0.95, 1.22]; P = 0.23) and PFS (RR = 1.15; 95%CI = [0.96, 1.37]; P = 0.13) rates to thoracotomy sleeve lobectomy. No significant heterogeneities were observed. VATS sleeve lobectomy yielded less surgical trauma than thoracotomy sleeve lobectomy and improved postoperative recovery without compromising oncological prognosis. Even though VATS sleeve lobectomy may consume more operation time, it could be recommended as an alternative to thoracotomy sleeve lobectomy for treating centrally located NSCLC in carefully selected cases.

A systematic review and meta-analysis of thoracoscopic versus thoracotomy sleeve lobectomy.

BackgroundOperative safety and oncologic adequacy of thoracoscopic sleeve lobectomy remain controversial. As such, the purpose of this meta-analysis was to evaluate evidence comparing thoracoscopy and thoracotomy in sleeve lobectomy for centrally located non-small cell lung cancer (NSCLC).MethodsElectronic searches of PubMed and Web of Science databases were undertaken from inception to March 2020. Comparative studies about thoracoscopic and thoracotomy sleeve lobectomy, with evaluation for perioperative outcomes and oncological results were identified. The following outcomes were measured in this meta-analysis: operating time, blood loss, numbers of lymph node, postoperative hospital stay, chest drainage time, postoperative complication rate, mortality, overall survival (OS). The standardized difference (SMD), relative risk (RR) and hazard ratio (HR) with 95% confidence intervals (CI) were pooled using Stata software.ResultsSix studies generating 281 thoracoscopy and 369 thoracotomy cases were finally included. There was no significant difference in intraoperative blood loss, number of resected lymph nodes, chest drainage time, postoperative complication rate and mortality between two groups. However, thoracoscopic sleeve lobectomy was associated with longer operation time (SMD 0.59, 95% CI: 0.14 to 1.03, P=0.010). And shorter postoperative hospital stays (SMD −0.24, 95% CI: −0.51 to 0.03, P=0.078) were observed in the thoracoscopy group with marginal significance. Furthermore, sleeve lobectomy via thoracoscopy could achieve comparable OS compared to that via thoracotomy (HR 0.69, 95% CI: 0.38 to 1.00; P<0.001). In addition, there were no evident publication bias in all observational outcomes.ConclusionsCurrent evidence suggests that thoracoscopic sleeve lobectomy is a safe and efficient surgical procedure for centrally located NSCLC, with comparable perioperative outcomes and equivalent oncological results compared to thoracotomy sleeve lobectomy.

Circulating Tumor DNA as a Prognostic Biomarker in Localized Non-small Cell Lung Cancer.

BackgroundRoutine clinical surveillance involves serial radiographic imaging following radical surgery in localized non-small cell lung cancer (NSCLC). However, such surveillance can detect only macroscopic disease recurrence and is frequently inconclusive. We investigated if detection of ctDNA before and after resection of NSCLC identifies the patients with risk of relapse, and furthermore, informs about response to management.MethodsWe recruited a total of 77 NSCLC patients. A high-throughput 127 target-gene capture technology and a high-sensitivity circulating single-molecule amplification and resequencing technology (cSMART) assay were used to detect the somatic mutations in the tumor tissues as well as the plasma of NSCLC patients before and after surgery to monitor for minimal residual disease (MRD). Kaplan-Meier and Cox regression analysis were performed to evaluate the relapse-free survival (RFS) and overall survival (OS) of patients with predictor variables.ResultsPatients with a higher stage (III/IV) and preoperative ctDNA-positive status demonstrated a significant 2.8-3.4-fold risk and 3.8-4.0-fold risk for recurrence and death, respectively. Preoperative ctDNA-positive patients associated with a lower RFS (HR = 3.812, p = 0.0005) and OS (HR = 5.004, p = 0.0009). Postoperative ctDNA-positive patients also associated with a lower RFS (HR = 3.076, p = 0.0015) and OS (HR = 3.195, p = 0.0053). Disease recurrence occurred among 63.3% (19/30) of postoperative ctDNA-positive patients. Most of these patients 89.5% (17/19) had detectable ctDNA within 2 weeks after surgery and was identified in advance of radiographic findings by a median of 12.6 months.ConclusionAdvanced stage and preoperative ctDNA-positive are strong predictors of RFS and OS in localized NSCLC patients undergoing complete resection. Postoperative detection of ctDNA increases chance to detect early relapse, thus can fulfill an important role in stratifying patients for immediate further treatment with adjuvant and neoadjuvant therapy.

Abstract 735: Sensitive detection of ctDNA in early stage non-small cell lung cancer patients with a personalized sequencing assay

Abstract Introduction Identification of minimal residual disease (MRD) following curative intervention of localized non-small cell lung cancer (NSCLC) holds promise for identifying patients who are at higher risk of relapse and who would benefit from adjuvant treatment. Current routine clinical practice involves serial radiographic imaging following surgery to detect macroscopic disease. Liquid biopsy can identify patients who have MRD without macroscopic disease. Currently available assays have only identified circulating tumor DNA (ctDNA) in a limited number of cases with early stage NSCLC. More sensitive methods are needed to accurately identify the majority of patients who will relapse. Here we evaluate the performance of InVision®MRD, a personalized sequencing assay for plasma cell-free DNA, for detection of ctDNA in patients with early-stage NSCLC undergoing treatment with curative intent. Methods InVision®MRD is a highly sensitive in vitro diagnostic assay, currently available for research use only (RUO), that can detect the presence of tumor DNA traces in cell-free DNA from plasma samples of cancer patients. InVision®MRD identifies tumor-specific variants from exome sequencing of tumor tissue and tracks them in plasma specimens by multiplex PCR and high-depth next-generation sequencing. We evaluated the detection of ctDNA in plasma samples collected from the LUng cancer - CIrculating tumor DNA (LUCID) study, which collected plasma samples from 100 patients with NSCLC stages I-III who underwent radical treatment with curative intent, either surgery or radiotherapy ± chemotherapy. Of patients in the LUCID study, 60% had stage I NSCLC and 40% patients had stage II/III disease, according to TNM 7th edition. Results To evaluate the InVision®MRD assay, a subset of samples from the LUCID study were analyzed. Samples were collected before and after surgery and chemo-radiotherapy from patients with early-stage NSCLC. Using multiplexed analysis of 48 patient-specific variants and high-depth sequencing, ctDNA was detected in 50% of pre-treatment samples analyzed from the first set of 18 patients, at ctDNA fractions ranging from 20 ppm (equivalent to 0.002%) to 19576 ppm (equivalent to 1.958%). Conclusions These findings highlight an opportunity to improve ctDNA detection for early stage NSCLC using a patient-specific plasma sequencing assay. Initial detection rates have reached 50% for patients with early-stage disease prior to treatment, including detection of ctDNA to levels as low as a few parts per million. Together with further data to be presented, this suggests a possible route to improving treatment for early stage NSCLC by detection of residual disease post treatment and for monitoring for early detection of relapse. Citation Format: Katrin Heider, Davina Gale, Andrea Ruiz-Valdepenas, Giovanni Marsico, Garima Sharma, Malcolm Perry, Robert Osborne, Karen Howarth, Tadd Lazarus, Viona Rundell, Jelena Belic, Jerome Wulff, Susan Harden, Doris M. Rassl, Robert C. Rintoul, Nitzan Rosenfeld. Sensitive detection of ctDNA in early stage non-small cell lung cancer patients with a personalized sequencing assay [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 735.

Extended sleeve-lobectomy for centrally located locally advanced non-small cell lung cancer is a feasible approach to avoid pneumonectomy.

BackgroundsThe aim of this study was to report our Institutional experience with extended sleeve lobectomy (ESL) in centrally located non-small cell lung cancer (NSCLC), focusing on technical details, post-operative results, recurrence and survival, to determine whether ESL can be accepted as a favorable alternative procedure to pneumonectomy (PN).MethodsTwenty-two consecutive patients undergoing ESL for centrally located tumors from January 2014 to June 2019 were prospectively enrolled.ResultsSix (27.3%) patients had been preoperatively considered unfit for PN. Neo-adjuvant chemotherapy was administered in 7 (31.8%) out of the 10 patients that showed a cN2 disease. According to Okada classification, 8 cases of type A ESL (resection of right upper plus middle lobe ± segment 6), one case of type B (resection of left upper lobe + segment 6) and 13 cases of type C (resection of left lower lobe + lingulectomy) ESL were performed. Concomitant pulmonary angioplasty was done in 7 (31.8%) patients. Complete resection was achieved in all patients. There was no postoperative mortality. Major postoperative complications developed in 2 (9.1%) patients (one small anastomotic dehiscence healed in few weeks, one pulmonary embolism). Complete long-term patency of the reconstructed airway was documented in all patients by fiber-optic bronchoscopy. At the median follow-up of 21 months (4–57 months), the recurrence rate was 54.5%, with 4 (18.2%) patients developing a loco-regional recurrence but no endobronchial or perianastomotic recurrence occurred. The overall 3-year survival rate was 45% with a median survival of 33 months.ConclusionsESL is a safe and effective procedure that should be considered a favorable alternative to PN whenever it may guarantee a complete resection.

Prognostic significance of low pectoralis muscle mass on preoperative chest computed tomography in localized non-small cell lung cancer after curative-intent surgery

ObjectivesThe impact of sarcopenia on the outcome in patients following resection of non-small cell lung cancer is yet to be fully determined. This study aimed to evaluate the clinical utility of a computed tomography-based pectoralis muscle assessment, which reflects sarcopenia, to predict the risk of postoperative outcomes. Materials and methodsThis retrospective study included 347 consecutive patients undergoing curative-intent resection of non-small cell lung cancer from 2009 to 2013. The pectoralis muscle index (pectoralis muscle area/body mass index) was assessed at the level of the fourth thoracic vertebra on chest axial images. The primary outcomes were compared between the lowest gender-specific quintile (sarcopenia) and the other quintiles according to the index. The prognostic significance of low pectoralis muscle index was calculated by the Cox proportional hazards regression model. A propensity score matching analysis was performed to adjust the differences in clinical characteristics. ResultsSixty-nine patients were identified with sarcopenia according to the lowest gender-specific quintile of pectoralis muscle index. Patients with sarcopenia exhibited worse 5-year overall survival rate compared with patients without sarcopenia (64.2 % vs. 86.7 %, P < 0.001). Even in stage I non-small cell lung cancer, the rate of 5-year overall survival in the sarcopenia group was lower than that in the non-sarcopenia group (74.2 % vs. 92.4 %, P = 0.001). Multivariate analysis revealed that low pectoralis muscle index was independently associated with adverse overall survival (hazard ratio: 2.09, 95 % confidence interval: 1.20–3.62, P = 0.009). After propensity score matching, the prognostic impact of sarcopenia based on low pectoralis muscle index was also robust for overall survival (hazard ratio: 3.23, 95 % confidence interval: 1.38–7.60, P = 0.007). ConclusionsLow pectoralis muscle index was significantly associated with poor long-term outcomes in patients with localized non-small cell lung cancer after curative surgery. This may help assist preoperative risk stratification and longitudinal management after surgery.

KEAP1/NFE2L2 mutations to predict local recurrence after radiotherapy but not surgery in localized non-small cell lung cancer.

9012 Background: Tumor genotyping in localized non-small cell lung cancer (NSCLC) is not broadly performed due to lack of actionable associations of mutations with treatment or outcome. We sought to identify recurrent mutations in localized NSCLC that are associated with local recurrence (LR) after radiotherapy (RT) or surgery. Methods: We identified consecutive patients with NSCLC treated with chemoradiotherapy (CRT), stereotactic ablative radiotherapy (SABR) or surgery from 2009-2018 at our institution with stage IA1-IIIC NSCLC who had genotyping performed on tumor tissue using a targeted gene panel. Our primary objective was to identify somatic tumor mutations that predicted LR after RT but not surgery. We also performed functional screening assays by expressing open reading frame constructs harboring patient-derived mutations in knock-out cell lines generated by CRISPR-Cas9 and evaluating effects on in vitro radioresistance. Results: We identified 232 consecutive patients with localized NSCLC (87.1% adenocarcinoma, 10.3% squamous, 2.3% other) who received tumor biopsy or resection specimen and underwent tumor genotyping. 47 patients with locally advanced NSCLC received CRT, 50 patients with early stage NSCLC received SABR, and 135 patients with early stage NSCLC underwent surgical resection. Of all recurrent mutations ( &gt; 5% mutation frequency), only mutations in Kelch-like ECH-associated protein 1 ( KEAP1) or Nuclear Factor Erythroid 2-Related Factor 2 ( NFE2L2) genes (K/NMUT) were significantly associated with LR after CRT or SABR, with 2-year LR in the combined RT cohort of 42.4% for K/NMUT versus 12.5% for wildtype (P = 0.005). Furthermore, K/NMUT were present in nearly half of all LR events. Strikingly, there was no significant difference in LR for K/NMUT tumors following CRT versus SABR (P = 0.47). Local recurrence was rare for patients who received surgery (n = 2) and was not associated with K/N mutation status (P = 0.60). Functional evaluation by expression of K/N mutations in knock-out cell lines revealed that LR only occurred in patients with mutations that induced radioresistance (i.e. pathogenic) but not passenger mutations (P = 0.04). In contrast to genotyping, NFE2L2 target gene expression analysis via RNA-seq did not predict LR (P = 0.93). Conclusions: Our findings suggest that KEAP1/NFE2L2 mutations are a predictive biomarker of clinical radioresistance and a dominant cause of LR after RT. Genotyping for KEAP1/NFE2L2 mutations could therefore facilitate treatment personalization in localized NSCLC.

Detection of residual disease and recurrence in early-stage non-small cell lung cancer (NSCLC) patients using sensitive personalized ctDNA sequencing assays.

e15560 Background: Detection of residual circulating tumour DNA (ctDNA) in patient plasma following curative intervention for localized non-small cell lung cancer (NSCLC) could identify patients who are at higher risk of relapse. These patients may benefit from adjuvant treatment, even if they have no macroscopic disease identified by radiographic imaging, which is the current standard of care. Here we evaluate the performance of the Inivata personalized sequencing assays to detect ctDNA in a cohort of 90 patients with early-stage NSCLC undergoing treatment with curative intent. Methods: The Inivata assay uses a highly sensitive next-generation sequencing platform, to identify tumor-specific variants from exome sequencing of tumor tissue and to track up to 48 patient-specific mutations in plasma specimens by multiplex PCR and ultra-high-depth next-generation sequencing. Samples from 90 patients with Stage I-III NSCLC who underwent radical treatment with curative intent, either surgery or radiotherapy ± chemotherapy, were collected as part of the LUng cancer - CIrculating tumor DNA (LUCID) study. Results: 350 plasma samples from 90 patients were analyzed using the Inivata assay, including samples collected before and after treatment and at subsequent follow-up visits. ctDNA was detected in pre-treatment samples in 38% of 32 patients (12/32) with Stage I NSCLC and in 90% of 21 patients (19/21) with Stage II/III disease, at allele fractions ranging from 6 parts per million (ppm, equivalent to 0.0006%) to over 20,000 ppm (equivalent to 2%). In plasma samples collected post-treatment, ctDNA was detected in close to 50% of cases. Conclusions: These findings highlight the Inivata assay is a sensitive method for detection of residual ctDNA and recurrence in early stage NSCLC. Initial detection rates ranged from 38% in Stage I disease to 90% for patients with Stage II/III disease prior to treatment, including detection of ctDNA to levels as low as a few parts per million. ctDNA was detected in at least one post-treatment timepoint in close to 50% patients. Together with additional data to be presented from the full 90 patient cohort, this suggests a possible route to improving treatment and designs of adjuvant trials for early stage NSCLC by detection of residual disease post-treatment and monitoring for early detection of relapse.

Radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC): A prospective, observational study.

e21065 Background: RP is a clinically challenging side effect following SBRT. The reported incidence of RP varies from 2.2% to 46.8%, depending on study design and different grading systems. We evaluated the grading systems for RP and identified possible predictive tests for RP. Furthermore, we estimated the correlation between RP and dosimetric measurements from the radiation therapy. Methods: Medically inoperable patients, n = 44, with peripherally located NSCLC stage I-II, were treated with SBRT, with a total dose of 45–56 Gy in 3–8 fractions. Median age was 75 years, 43.2% were female and 60% had moderate to very severe COPD. Follow up included physical examination by pulmonologist, spirometry and single-breath lung diffusing capacity (DLCO) and CT evaluation at baseline and 1.5, 3, 6, 9 and 12 months after SBRT. Results: We constructed three groups for grading RP based on CTCAE version 5.0 and imaging changes according to EORTC (LENT-SOMA) Non-RP (asymptomatic or mild symptoms and slight imaging changes, n = 19, 43%), Asymptomatic, radiology-only RP (asymptomatic or mild symptoms, increased density imaging changes, n = 17, 39%) and Symptomatic and radiology-detected RP (moderate and severe symptoms and increased density imaging changes, n = 8, 18%). Active smokers and patients with emphysema were overrepresented in non-RP group. In the symptomatic RP group, DLCO and FEV1 dropped almost 5% 4-6 weeks after SBRT, before symptoms and imaging changes, and DLCO, FVC and FEV1 dropped significantly at 3 months (table). Development of RP was associated with critical dose-volume parameter 1000ccm and 1500ccm. Several dosimetric parameters significantly negative correlate with FVC-drop at 1 and 3 months only in symptomatic RP. Conclusions: Active smokers and patients with emphysema have less propensity of RP. Symptomatic RP is seen with a presymptomatic drop in FEV1 and DLCO occurring 4-6 weeks after SBRT. Critical dose-volume parameter is important parameters for RP. Correlation between dosimetric parameters and FVC-drop in symptomatic RP. Clinical trial information: NCT02428049 . [Table: see text]

Prognostic factors of local control and disease free survival in centrally located non-small cell lung cancer treated with stereotactic body radiation therapy

Background: Stereotactic body radiation therapy (SBRT) results in high local control (LC) rates in patients with non-small cell lung cancer (NSCLC). For central lung tumors, risk-adapted fractionation schedules are used and underdosage to the Planned Target Volume (PTV) is often accepted to respect the dose constraints of the organs at risk in order to avoid high rates of toxicity. The purpose of this study was to analyze the effect of PTV underdosage and other possible prognostic factors on local- and disease control after SBRT in patients with central lung tumors.Material and Methods: Patients with centrally located NSCLC treated with SBRT were included. The doses were converted into biologically equivalent dose using α/β-value of 10 Gy (BED10). Underdosage to the PTV was defined as the (percentage of) PTV receiving less than 100 Gy BED10; (%)PTV < 100 BED10. Potential prognostic factors for LC and Disease Free Survival (DFS) were evaluated using Cox regression analysis.Results: Two hundred and twenty patients received ≤12 fractions of SBRT. LC-rates were 88% at 2 years and 81% at 3 years. Twenty-seven patients developed a local recurrence. Both the PTV < 100 BED10 and %PTV < 100 BED10 were not prognostic for LC. Tumor size and forced expiratory volume in 1 second (FEV1) were independently prognostic for LC. Disease progression was reported in 75 patients with DFS-rates of 66% at 2 years and 56% at 3 years. Disease recurrence was independent significantly associated with larger tumor diameter, lower lobe tumor location and decreased FEV1. Grade 4–5 toxicity was reported in 10 patients (8 with ultra-central tumors) and was fatal in at least 3 patients.Conclusion: Decrease in tumor coverage was not correlated with the local recurrence probability. The LC and DFS were promising after SBRT of centrally located NSCLC with tumor size, FEV1 and tumor location (for DFS only) as prognostic factors.

The Effects of Ezh2 Mutation on Kras‐Driven Adenocarcinoma

Lung cancer is the deadliest form of cancer worldwide. Non‐small cell lung cancer (NSCLC) is the most common type of lung cancer, constituting an estimated 84% of diagnoses. Conducting research regarding the metastasis of lung adenocarcinomas is especially pertinent, as the 5‐year survival rate for localized NSCLC is an estimated 50% versus 6% in metastatic lung cancer. Here we investigate the activation effects of Polycomb Repressive Complex 2 (PRC2), an epigenetic regulator commonly found to be dysregulated in human lung cancer, as a driver of metastasis. We employed genetically engineered mouse models harboring activating point mutations in Kras and inactivating mutations in the p53 pathway (KP model) which develop lung adenocarcinomas but exhibit low penetrance and long latency for metastasis. As a resolution, our lab has generated a KPE mouse model which carries a mutation that induces Ezh2 activation, a core component of PRC2. We hypothesize that KPE is an effective and robust metastatic model which displays a shorter latency period than previously established lung adenocarcinoma models. In this project we used a histological approach to characterize morphological properties of primary tumors as well as distinct lymph node metastases in KPE mouse models. By visualizing cellular phenotypes through Hematoxylin &amp; Eosin staining, we intended to quantify tumor area and composition of lymphatic micrometastases. The results illustrated that mice with the Ezh2 mutation in addition to the Kras and p53 mutations experienced a shorter latency period as well as a higher occurrence of lymph node metastases as opposed to the KP model.Support or Funding InformationThis project is supported in part by National Science Foundation Grant 1758007.

Place de l’immunothérapie dans le cancer bronchique non à petites cellules localement avancé

Concomitant radiochemotherapy has been the standard of care for unresectable stage III non-small cell lung cancer (NSCLC), irrespective of histological sub-type or molecular characteristics. Currently, only 15–30 % of patients are alive five years after radiochemotherapy, and this figure remains largely unchanged despite multiple phase III randomised trials. In recent years, immune-checkpoint blockades with anti-PD-(L)1 have revolutionised the care of metastatic NSCLC, becoming the standard front- and second-line strategy. Several preclinical studies reported an increased tumour antigen release, improved antigen presentation, and T-cell infiltration in irradiated tumours. Immunotherapy has therefore recently been evaluated for patients with locally advanced stage III NSCLC. Following the PACIFIC trial, the anti-PD-L1 durvalumab antibody has emerged as a new standard consolidative treatment for patients with unresectable stage III NSCLC whose disease has not progressed following concomitant platinum-based chemoradiotherapy. Immunoradiotherapy therefore appears to be a promising association in patients with localised NSCLC. Many trials are currently evaluating the value of concomitant immunotherapy and chemoradiotherapy and/or consolidative chemotherapy with immunotherapy in patients with locally advanced unresectable NSCLC.

Response evaluation after stereotactic ablative radiotherapy for localised non-small-cell lung cancer: an equipoise of available resource and accuracy.

There is growing evidence supporting the use of stereotactic ablative radiotherapy (SABR) on the treatment of localised stage non-small-cell lung cancer (NSCLC). Distinctive imaging challenges are posed post-SABR treatment. Thus, it is imperative to provide guidance on assessing treatment response, especially for new adopters. This commentary is about filling a gap in response evaluation after SABR for localised NSCLC.

Sleeve lobectomy compared with pneumonectomy for operable centrally located non-small cell lung cancer: a meta-analysis.

The purpose of this meta-analysis was to evaluate evidence comparing sleeve lobectomy (SL) and pneumonectomy (PN) in the treatment of non-small cell lung cancer (NSCLC). The English literature search was undertaken in January 2018 and included studies dating back to 1996. Comparative studies were identified, evaluating survival, local recurrence, and distant recurrence rates, operative mortality, 30-day mortality, as well as complications. A pooled odds ratio (OR) and 95% confidence intervals (95% CI) were calculated with either the random or fixed-effect model. A total of 27 studies were identified, with publication dates between 1996 and 2018. These 27 studies included a total of 14,194 patients: 4,145 treated with SL and 10,049 treated with PN. The overall survival was significantly higher in the SL group compared to the PN one at 1, 3, 5 years. In patients with N0 and N1 disease, 5-year survival rates following SL exceeded those following PN. There was no statistically significant difference in the 3-, 5-year overall survival of N2 patients, according to the extent of surgery. The PN group had a higher rate of operative mortality, 30-day mortality and distant recurrence incidence. However, no statistical difference in complications and local recurrence between SL and PN were observed. SL is an effective treatment option for hilar NSCLC with improved long-term survival compared to PN, with no increase of recurrence rate or postoperative complications. Furthermore, N2 disease is an important factor related to survival, and lymph node downstaging is a favorable prognostic factor.

How should we decide the optimum intraoperative fluid and colloid usage in pulmonary resection?

Lung cancer is the leading cause of cancer death throughout the world and pulmonary resection remains a major surgical procedure for the cure of localized non-small cell lung cancer. Respiratory complications are still the major cause of mortality and morbidity after lung resection. Pneumonia and acute respiratory distress syndrome (ARDS) are responsible for the great part of respiratory-related deaths after lung resection (1).

Incidentally Detected Malignancies in Lung Transplant Explants.

Background.Active malignancy diagnosed within 5 years is an absolute contraindication for lung transplantation. In this study, we evaluated the rate of incidental malignancies detected in explanted lungs at our institution and assessed the posttransplant survival in patients with nonsmall cell lung cancer (NSCLC).Methods.A retrospective chart review of lung transplant recipients at our institution from February 1999 to June 2017 was conducted. A literature review was performed to evaluate the prevalence and survival outcomes in patients with unexpected malignancies.Results.From 407 patients who underwent lung transplantation, 9 (2.2%) were discovered to have malignant neoplasms. There were 3 cases of adenocarcinoma, 3 cases of adenocarcinoma in situ, 2 cases of squamous cell carcinoma, and 1 case of metastatic renal cell carcinoma. An extensive literature review found 12 case reports or case series reporting malignancy discovered at the time of lung transplantation. The overall prevalence of incidental neoplasms among 6746 recipients is around 1.5% (n = 103). The most common neoplasms discovered included adenocarcinoma (n = 56, 54%) and squamous cell carcinoma (n = 29, 28%). The overall 3-year survival was 54.4% for patients with localized NSCLC compared to 5.7% for those with nonlocalized disease.Conclusions.Unidentified malignancies occur despite aggressive radiographic surveillance with poor posttransplant outcomes in patients with advanced malignancy. Malignancy-related radiographic findings may be missed pretransplant secondary to architectural distortion of lung parenchyma related to end-stage lung disease or because of the critical timing of surgery when donor lungs are available.

P1.17-40 Clinical Implications of Using Circulating Tumor DNA to Assess Minimal Residual Disease (MRD) in Patients with NSCLC After Definitive Treatment

Circulating tumor DNA (ctDNA) has been used to identify driver genomic alterations during treatment of metastatic nonsmall cell lung cancer (NSCLC). Recent studies have also demonstrated the role of ctDNA to monitor response to therapy. Here we performed an analysis on a cohort of NSCLC patients (pts) with localized disease who underwent ctDNA testing after definitive treatments to determine whether ctDNA can be used as a marker of MRD. Between 2015-2019, 70 pts with localized NSCLC received ctDNA testing. ctDNA testing was done using the next generation sequencing (NGS) panel of 73 genes via digital sequencing technology (Guardant360). Statistical analysis was performed to determine which factors were associated with ctDNA levels and recurrence free survival (RFS). Of the 70 pts analyzed, 26 pts had ctDNA testing performed after definitive treatment. Median duration of follow up was 22 months (range: 3 to 36). 26% (n = 7) had stage I disease, 30% (n = 8) had stage II disease, and 42% (n = 11) had stage III disease. 81% (n = 21) were adenocarcinoma while 19% (n = 5) were squamous cell carcinoma. 42% (n = 11) had no recurrence during our observation time, while 58% (n = 15) experienced progression. For definitive treatments, 38% (n = 10) underwent surgery alone, 35% (n = 9) underwent surgery with adjuvant chemotherapy, 15% (n = 4) underwent chemoradiation therapy, 8% (n=2) underwent surgery followed by radiation, and 4% (n=1) underwent surgery with adjuvant chemoradiation prior to their ctDNA levels [variant allele frequency (VAF)] being drawn. Of these, 15% (n = 4) tested negative for any ctDNA, while 85% (n = 22) were positive. Only one of the pts with undetectable levels of ctDNA experienced recurrence of cancer 34 months after definitive treatment with surgery followed by chemotherapy. 13 among 22 pts with detectable ctDNA had recurrence (median time to recurrence = 6.3 months). Kaplan-Meir survival analysis revealed a trend toward significant association between the presence of detectable ctDNA and RFS (p = 0.10). Our analysis demonstrates that ctDNA could potentially be used as a marker to assess MRD following definitive treatment for localized NSCLC.

P2.04-19 Neoadjuvant Chemotherapy Is Associated with Immunogenic Cell Death and Increased T Cell Infiltration in Early-Stage NSCLC

Recent success using immune checkpoint blockade (ICB) in the metastatic setting has raised the need to understand the immune microenvironment (IME) in early-stage disease. Moreover, pre-clinical evidence suggests that cytotoxic agents can modulate this IME. A recent study conducted by our group showed that non-small cell lung cancer (NSCLC) patients who received neoadjuvant chemotherapy followed by surgery (NCT), as compared to patients who received upfront surgery (US), had higher densities of CD3+ lymphocytes and CD68+ tumor-associated macrophages (TAMs). CD3+CD4+ lymphocytes and TAMs also correlated with better clinical outcomes. In this study, we explored the relationships between NCT and the IME by harvesting tumor samples of multiple surgical NSCLC cohorts. The PROSPECT microarray database was queried in NCT (n=45) and US (n=200) patients to investigate differentially expressed genes related to immunogenic cell death (ICD), susceptibility to CD8+ T cell and NK cell cytotoxicity, priming of antigen presenting cells, immunosuppressive enzymes and intra-tumoral cytokines. Available data from the ImmunogenomiC prOfiling of NSCLC (ICON) and other surgical NSCLC cohorts was evaluated to determine: 1) differential immune profiling using FACS (NCT=17; US=39) and multiplex IHC imaging (NCT=10; US=72); 2) plasma circulating cytokines (NCT=18; US=73); 3) tumor mutational burden (TMB) (NCT=40; US=61). Participants who received NCT or US were excluded according to these criteria: 1) concurrent treatment in addition to NCT; 2) sarcomatoid and small cell histologies; 3) clinical or pathological TNM Stage 4 disease; 4) synchronous malignancies other than lung. PROSPECT NCT patients expressed increased damage-associated molecular pattern (DAMP) genes (HSPA2, HSPA4, HSPE1, and S100A2; p<0.05) and T cell-related chemotaxis and antigen presentation genes (CXCR7, CD1A; p<0.05). Concordantly, the ICON cohort FACS results showed that NCT patients display increases in: 1) infiltration of CD8+ T cells (p=0.004); 2) proliferating Ki67+CD8+ T cells (p=0.02); 3) tissue resident memory CD8+CD103+ (p=0.02) and CD4+CD103+ non-Treg cells (p=0.01). Trends from the ICON multiplex IHC also highlighted increases in CD8+ T cells (p=0.09), CD20+ cells (p=0.08), as well as PD-L1+ malignant cells (p=0.08) and PD-L1+ TAMs (p=0.08) in NCT patients, the latter finding being supported by increased circulating MCP-1 (p=0.03). TMB was similar between NCT and US groups (p=0.912). Our data provides the first evidence of ICD (i.e., increased DAMP gene expression) following NCT in human early-stage NSCLC. Furthermore, our data highlights the association of NCT with a favorable IME (i.e., increased T cell infiltration), supporting the rationale of NCT and ICB combinations in localized NSCLC.

Cancer du poumon et irradiation ganglionnaire prophylactique : un débat clos ?

Lung cancer treatment is a heavy workload for radiation oncologist and that field showed many evolutions over the last two decades. The issue about target volume was raised when treatment delivery became more precise with the development of three-dimensional conformal radiotherapy. Initially based upon surgical series, numerous retrospective and prospective studies aimed to evaluate the risk of elective nodal failure of involved-field radiotherapy compared to standard large field elective nodal irradiation. In every setting, locally advanced non-small cell lung cancer, localized non-small cell lung cancer, localized small cell lung cancer, exclusive chemoradiation or postoperative radiotherapy, most of the studies showed no significant difference between involved-field radiotherapy or elective nodal irradiation with elective nodal failure rate under 5% at 2 years, provided staging had been done with modern imaging and diagnostic techniques (positron emission tomography scan, endoscopy, etc.). Moreover, if reducing irradiated volumes are safe regarding recurrences, involved-field radiotherapy allowed dose escalation while reducing acute and late oesophageal, cardiac and pulmonary toxicities. Consequently, major clinical trials involving radiotherapy initiated in the last two decades and international clinical guidelines recommended omission of elective nodal irradiation in favour of in-field radiotherapy.