Longitudinal analysis of PD-L1 expression in patients with relapsed NSCLC.

BACKGROUND: The use and approval of immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) depends on PD-L1 expression in the tumor tissue. Nevertheless, PD-L1 often fails to predict response to treatment. One possible explanation could be a change in PD-L1 expression during the course of the disease and the neglect of reassessment. The purpose of this study was a longitudinal analysis of PD-L1 expression in patients with relapsed NSCLC. METHODS: We retrospectively analyzed PD-L1 expression in patients with early-stage NSCLC and subsequent relapse in preoperative samples, matched surgical specimens and biopsy samples of disease recurrence. Ventana PD-L1 (SP263) immunohistochemistry assay was used for all samples. PD-L1 expression was scored based on clinically relevant groups (0%, 1%-49%, and ≥50%). The primary endpoint was the change in PD-L1 score group between preoperative samples, matched surgical specimens and relapsed tumor tissue. RESULTS: 395 consecutive patients with stages I-III NSCLC and 136 (34%) patients with a subsequent relapse were identified. For 87 patients at least two specimens for comparison of PD-L1 expression between early stage and relapsed disease were available. In 72 cases, a longitudinal analysis between preoperative biopsy, the surgically resected specimen and biopsy of disease recurrence was feasible. When comparing preoperative and matched surgical specimens, a treatment-relevant conversion of PD-L1 expression group was found in 25 patients (34.7%). Neoadjuvant treatment showed no significant effect on PD-L1 alteration (p=0.39). In 32 (36.8%) out of 87 cases, a change in PD-L1 group was observed when biopsies of disease relapse were compared with early-stage disease. Adjuvant treatment was not significantly associated with a change in PD-L1 expression (p=0.53). 39 patients (54.2%) showed at least 1 change into a different PD-L1 score group during the course of disease. 14 patients (19.4%) changed the PD-L1 score group twice, 5 (6.9%) of them being found in all different score groups. CONCLUSION: PD-L1 expression shows dynamic changes during the course of disease. There is an urgent need for consensus guidelines to define a PD-L1 testing strategy including time points of reassessment, the number of biopsies to be obtained and judgment of surgical specimens.

Expanding Broad Molecular Reflex Testing in Non-Small Cell Lung Cancer to Squamous Histology.

Due to the success story of biomarker-driven targeted therapy, most NSCLC guidelines agree that molecular reflex testing should be performed in all cases with non-squamous cell carcinoma (non-SCC). In contrast, testing recommendations for squamous cell carcinoma (SCC) vary considerably, specifically concerning the exclusion of patients of certain age or smoking status from molecular testing strategies. We performed a retrospective single-center study examining the value of molecular reflex testing in an unselected cohort of 316 consecutive lung SCC cases, tested by DNA- and RNA-based next-generation sequencing (NGS) at our academic institution between 2019 and 2023. Clinicopathological data from these cases were obtained from electronic medical records and correlated with sequencing results. In 21/316 (6.6%) cases, we detected an already established molecular target for an approved drug. Among these were seven cases with an EGFR mutation, seven with a KRAS G12C mutation, four with an ALK fusion, two with an EGFR fusion and one with a METex14 skipping event. All patients harboring a targetable alteration were >50 years of age and most of them had >15 pack-years, questioning restrictive molecular testing strategies. Based on our real-world data, we propose a reflex testing workflow using DNA- and RNA-based NGS that includes all newly diagnosed NSCLC cases, irrespective of histology, but also irrespective of age or smoking status.

Assessing the Performance of a Novel Stool-Based Microbiome Test That Predicts Response to First Line Immune Checkpoint Inhibitors in Multiple Cancer Types.

The intestinal microbiome is by now an undebatable key player in the clinical outcome of ICI therapies. However, no microbiome profiling method to aid therapy decision is yet validated. We conducted a multi-centric study in patients with stage III/IV melanoma, NSCLC, or RCC receiving ICI treatment. The stool microbiome profile of 63 patients was analyzed with BiomeOne®, a microbiome-based algorithm that anticipates whether a patient will achieve clinical benefit with ICIs prior to therapy initiation. Classification of patient samples as Rs and NRs was achieved with a sensitivity of 81% and a specificity of 50% in this validation cohort. An ICI-favorable response was characterized by an intestinal microbiome rich in bacteria such as Oscillospira sp., Clostridia UCG-014, Lachnospiraceae UCG-010 sp., Prevotella copri, and a decrease in Sutterella sp., Lactobacillales, and Streptococcus sp. Patients who developed immune-related adverse events (irAEs) had an overall increased microbial diversity and richness, and a stool microbiome depleted in Agathobacter. When compared with the programmed death-ligand 1 (PD-L1) expression test in the subcohort of NSCLC patients (n = 38), BiomeOne® exhibited a numerically higher sensitivity (78.6%) in identifying responders when compared with the PD-L1 test (67.9%). This study provides an evaluation of BiomeOne®, the first microbiome-based test for prediction of ICI response, to achieve market authorization. Validation with further indications and expansion to other microbiome-based interventions will be essential to bring microbiome-based diagnostics into standard clinical practice.

Characteristics and Treatment Outcomes in Advanced-Stage Non-Small Cell Lung Cancer Patients with a KRAS G12C Mutation: A Real-World Study.

About 15% of patients with non-small cell lung cancer (NSCLC) harbor the Kirsten rat sarcoma homolog G12C mutation (KRASG12C). Selective KRASG12C inhibitors offer new treatment opportunities, but little is known about the prevalence, characteristics, and outcomes of standard-of-care treatment (SOC) in this population. We retrospectively assessed the clinicopathological features of patients with KRASG12C-mutated advanced NSCLC and responses to SOC at two high-volume centers in Austria. Out of 2495 NSCLC patients tested, we identified 174 patients with advanced-stage disease carrying a KRASG12C mutation. Most patients were ≥65 years old (55%), heavy smokers (55%), and presented with comorbidities. The most frequent co-alteration was TP53 (18%). PD-L1 expression was high (TPS ≥ 50%) in 31%, very high (TPS ≥ 90%) in 11%, and negative in 31% of patients. A total of 138 patients (79%) received oncologic systemic treatment. The most common first-line therapy (1 L) was anti-PD-1/PD-L1 plus platinum-based chemotherapy. Median overall survival measured from 1 L treatment was 15.3 months (95% CI, 8.6-21.9), 9.4 (95% CI, 5.3-13.5) from 2 L treatment, and 8.4 (95% CI, 1.7-15.1) from 3 L treatment. The time-to-next-treatment was 8.4 (95% CI, 5.2-11.6) from 1 L and 6.1 (95% CI, 2.7-9.7) months from 2 L to 3 L. These poor outcomes underscore the need for the implementation of new treatment options and for specific molecular testing.

Patterns of Peripheral Blood B-Cell Subtypes Are Associated With Treatment Response in Patients Treated With Immune Checkpoint Inhibitors: A Prospective Longitudinal Pan-Cancer Study.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized systemic anti-tumor treatments across different types of cancer. Nevertheless, predictive biomarkers regarding treatment response are not routinely established yet. Apart from T-lymphocytes, the humoral immunity of B-lymphocytes is studied to a substantially lesser extent in the respective setting. Thus, the aim of this study was to evaluate peripheral blood B-cell subtypes as potential predictors of ICI treatment response. Methods: Thirty-nine cancer patients receiving ICI therapy were included into this prospective single-center cohort study. All had a first blood draw at the date before treatment initiation and a second at the time of first response evaluation (after 8-12 weeks). Seven different B-cell subtypes were quantified by fluorescence-activated cell sorting (FACS). Disease control- (DCR) and objective response rate (ORR) were co-primary study endpoints. Results: Overall, DCR was 48.7% and ORR was 25.6%, respectively. At baseline, there was no significant association of any B-cell subtype with neither DCR nor ORR. At the first response evaluation, an increase in the frequency of CD21- B-cells was a statistically significant negative predictor of response, both regarding DCR (OR=0.05, 95%CI=0.00-0.67, p=0.024) and ORR (OR=0.09, 95%CI=0.01-0.96, p=0.046). An increase of the frequency of switched memory B-cells was significantly associated with reduced odds for DCR (OR=0.06, 95%CI=0.01-0.70, p=0.025). Patients with an increased frequency of naïve B-cells were more likely to benefit from ICI therapy as indicated by an improved DCR (OR=12.31, 95%CI=1.13-134.22, p=0.039). Conclusion: In this study, certain B-cell subpopulations were associated with ICI treatment response in various human cancer types.

Evaluation of autoantibodies as predictors of treatment response and immune-related adverse events during the treatment with immune checkpoint inhibitors: A prospective longitudinal pan-cancer study.

BACKGROUND: The presence of autoantibodies in the serum of cancer patients has been associated with immune-checkpoint inhibitor (ICI) therapy response and immune-related adverse events (irAEs). A prospective evaluation of different autoantibodies in different cancer entities is missing. MATERIALS AND METHODS: In this prospective cohort study, we included a pan-cancer cohort of patients undergoing ICI treatment and measured a comprehensive panel of autoantibodies at treatment start and at the time point of first response evaluation. The presence and induction of autoantibodies (ANA, ENA, myositis, hepatopathy, rheumatoid arthritis) in different cancer entities were assessed and the association between autoantibodies and disease control rate (DCR), objective response rate (ORR), and progression-free survival (PFS), as well as the development of grade 3 or higher irAEs were evaluated by logistic regression models, cox proportional hazard models, and Kaplan-Meier estimators. RESULTS: Of 44 patients with various cancer entities, neither the presence of any positive autoantibody measurement nor the presence of positive antinuclear antibodies (ANA) [≥1:80] at baseline was associated with the examined clinical endpoints (DCR, ORR, PFS) in univariable and multivariable analyses. After 8-12 weeks of ICI treatment, DCR, ORR, and PFS did not significantly differ between patients with and without any positive autoantibody measurement or positive ANA titers. The frequency of irAEs did not differ depending on autoantibody status of the patients. CONCLUSION: Autoantibodies at treatment initiation or induction after 8-12 weeks of ICI treatment are not associated with treatment efficacy as indicated by DCR, ORR, and PFS or higher grade irAEs.

Real-world experience with anti-PD-1/PD-L1 monotherapy in patients with non-small cell lung cancer : A retrospective Austrian multicenter study.

OBJECTIVE: As real-world data regarding immunotherapy for non-small cell lung cancer are lacking for Austria, we conducted a retrospective study in six hospitals to present data from real-world practice. METHODS: Patients with metastatic non-small cell lung cancer were stratified into two groups, either patients with first-line pembrolizumab monotherapy (cohort 1) or patients with second-line nivolumab, pembrolizumab or atezolizumab monotherapy (cohort 2). Primary outcome measures were objective response rate and overall survival. A matched-pair analysis was performed to compare overall survival to patients from the Tyrolean Lung Cancer Project as a historical control group. RESULTS: In total, 89 patients were identified, 42 patients in cohort 1 and 47 patients in cohort 2. The objective response rates were 43.3% and 31.4%, respectively. The median overall survival was 17.0 months (95% CI 11.7-21.5 months) in cohort 1 and 18.7 months (95% CI 9.5-23.4 months) in cohort 2. Treatment-related adverse events grades 3 and 4 were reported in 11.2% of patients. The matched-pair analysis showed a median overall survival of 15.2 months (95% CI 7.6-20.4 months) for first-line pembrolizumab monotherapy compared to 9.8 months (95% CI 7.8-11.6 months) for the historical control (p = 0.43). In cohort 2, a median overall survival of 20.3 months (95% CI 6.9-26.2 months) for second-line immunotherapy compared to 5.4 months (95% CI 3.2-11.7 months) for the historical control (p = 0.18) was shown. CONCLUSION: The results are comparable with other real-world studies and, when matched to historical controls, support the improvement in outcomes made possible by these agents.

Immune Aging and Immunotherapy in Cancer.

Immune functions decline as we age, while the incidence of cancer rises. The advent of immune checkpoint blockade (ICB) has not only revolutionized cancer therapy, but also spawned great interest in identifying predictive biomarkers, since only one third of patients show treatment response. The aging process extensively affects the adaptive immune system and thus T cells, which are the main target of ICB. In this review, we address age-related changes regarding the adaptive immune system with a focus on T cells and their implication on carcinogenesis and ICB. Differences between senescence, exhaustion, and anergy are defined and current knowledge, treatment strategies, and studies exploring T cell aging as a biomarker for ICB are discussed. Finally, novel approaches to improve immunotherapies and to identify biomarkers of response to ICB are presented and their potential is assessed in a comparative analysis.

Selpercatinib in RET fusion-positive non-small-cell lung cancer (SIREN): a retrospective analysis of patients treated through an access program.

INTRODUCTION: Rearranged during transfection (RET) gene fusions are rare genetic drivers in non-small cell lung cancer (NSCLC). Selective RET-inhibitors such as selpercatinib have shown therapeutic activity in early clinical trials; however, their efficacy in the real-world setting is unknown. METHODS: A retrospective efficacy and safety analysis was performed on data from RET fusion-positive NSCLC patients who participated in a selpercatinib access program (named patient protocol) between August 2019 and January 2021. RESULTS: Data from 50 patients with RET fusion-positive advanced NSCLC treated with selpercatinib at 27 centers in 12 countries was analyzed. Most patients were Non-Asian (90%), female (60%), never-smokers (74%), with a median age of 65 years (range, 38-89). 32% of the patients had known brain metastasis at the time of selpercatinib treatment. Overall, 13 patients were treatment-naïve, while 37 were pretreated with a median of three lines of therapy (range, 1-8). The objective response rate (ORR) was 68% [95% confidence interval (CI), 53-81] in the overall population. The disease control rate was 92%. The median progression-free survival was 15.6 months (95% CI, 8.8-22.4) after a median follow-up of 9 months. In patients with measurable brain metastases (n = 8) intracranial ORR reached 100%. In total, 88% of patients experienced treatment-related adverse events (TRAEs), a large majority of them being grade 1 or 2. The most common grade ⩾ 3 TRAEs were increased liver enzyme levels (in 10% of patients), prolonged QTc time (4%), abdominal pain (4%), hypertension (4%), and fatigue/asthenia (4%). None of patients discontinued selpercatinib treatment for safety reasons. No new safety concerns were observed, nor where there any treatment-related death. CONCLUSIONS: In this real-world setting, the selective RET-inhibitor selpercatinib demonstrated durable systemic and intracranial antitumor activity in RET fusion-positive NSCLC and was well tolerated.

Reflex testing in non-small cell lung carcinoma using DNA- and RNA-based next-generation sequencing-a single-center experience.

BACKGROUND: Targeted treatment modalities for non-small cell lung carcinoma (NSCLC) patients are expanding rapidly and demand a constant adaptation of molecular testing strategies. In this regard, broad reflex testing via next-generation sequencing (NGS) might have several advantages. However, real-world data regarding practical feasibility and clinical relevance are scarce, especially for RNA-based NGS. METHODS: We performed a retrospective study comparing NGS use in two consecutive years (2019 and 2020). In 2019, reflex testing mainly consisted of DNA-based NGS for mutations and immunohistochemistry (IHC) for ALK, ROS1, and NTRK fusion products. At the beginning of 2020, our approach has changed, with DNA- and RNA-based NGS panels now being simultaneously performed. This change in protocol allowed us to retrospectively evaluate if broad molecular reflex testing brings additional value to lung cancer patients. RESULTS: Within the whole cohort (n=432), both DNA- and RNA-based NGS yielded almost always evaluable results. Only in 6 cases, the RNA content was too little for an appropriate analysis. After integrating RNA-based NGS in the reflex testing approach, the number of detected fusions increased significantly (2.6% vs. 8.2%; P=0.0021), but also more patients received targeted therapies. Furthermore, exceedingly rare alterations were more likely to be detected, including the so far undescribed EGFR-NUP160 fusion. CONCLUSIONS: Our study demonstrates that a comprehensive approach to reflex NGS testing is practically feasible and clinically relevant. Including RNA-based panels in the reflex testing approach results in more detected fusions and more patients receiving targeted therapies. Additionally, this broad molecular profiling strategy identifies patients with emerging biomarkers, underscoring its usefulness in the rapidly evolving landscape of targeted therapies.

Malignant peritoneal mesothelioma: prognostic significance of clinical and pathologic parameters and validation of a nuclear-grading system in a multi-institutional series of 225 cases.

Malignant peritoneal mesothelioma historically carried a grim prognosis, but outcomes have improved substantially in recent decades. The prognostic significance of clinical, morphologic, and immunophenotypic features remains ill-defined. This multi-institutional cohort comprises 225 malignant peritoneal mesotheliomas, which were assessed for 21 clinical, morphologic, and immunohistochemical parameters. For epithelioid mesotheliomas, combining nuclear pleomorphism and mitotic index yielded a composite nuclear grade, using a previously standardized grading system. Correlation of clinical, morphologic, and immunohistochemical parameters with overall and disease-free survival was examined by univariate and multivariate analyses. On univariate analysis, longer overall survival was significantly associated with diagnosis after 2000 (P = 0.0001), age <60 years (P = 0.0001), ECOG performance status 0 or 1 (P = 0.01), absence of radiographic lymph-node metastasis (P = 0.04), cytoreduction surgery (P < 0.0001), hyperthermic intraperitoneal chemotherapy (P = 0.0001), peritoneal carcinomatosis index <27 (P = 0.01), absence of necrosis (P = 0.007), and epithelioid histotype (P < 0.0001). Among epithelioid malignant mesotheliomas only, longer overall survival was further associated with female sex (P = 0.03), tubulopapillary architecture (P = 0.005), low nuclear pleomorphism (P < 0.0001), low mitotic index (P = 0.0007), and low composite nuclear grade (P < 0.0001). On multivariate analyses, the low composite nuclear grade was independently associated with longer overall and disease-free survival (P < 0.0001). Our data further clarify the interactions of clinical and pathologic features in peritoneal mesothelioma prognosis and validate the prognostic significance of a standardized nuclear-grading system in epithelioid malignant mesothelioma of the peritoneum.

Later-Line Treatment with Lorlatinib in ALK- and ROS1-Rearrangement-Positive NSCLC: A Retrospective, Multicenter Analysis.

In clinical practice, patients with anaplastic lymphoma kinase (ALK)-rearrangement-positive non-small-cell lung cancer commonly receive sequential treatment with ALK tyrosine kinase inhibitors. The third-generation agent lorlatinib has been shown to inhibit a wide range of ALK resistance mutations and thus offers potential benefit in later lines, although real-world data are lacking. This multicenter study retrospectively investigated later-line, real-world use of lorlatinib in patients with advanced ALK- or ROS1-positive lung cancer. Fifty-one patients registered in a compassionate use program in Austria, who received second- or later-line lorlatinib between January 2016 and May 2020, were included in this retrospective real-world data analysis. Median follow-up was 25.3 months. Median time of lorlatinib treatment was 4.4 months for ALK-positive and 12.2 months for ROS-positive patients. ALK-positive patients showed a response rate of 43.2%, while 85.7% percent of the ROS1-positive patients were considered responders. Median overall survival from lorlatinib initiation was 10.2 and 20.0 months for the ALK- and ROS1-positive groups, respectively. In the ALK-positive group, lorlatinib proved efficacy after both brigatinib and alectinib. Lorlatinib treatment was well tolerated. Later-line lorlatinib treatment can induce sustained responses in patients with advanced ALK- and ROS1-positive lung cancer.

C-Reactive Protein (CRP) Levels in Immune Checkpoint Inhibitor Response and Progression in Advanced Non-Small Cell Lung Cancer: A Bi-Center Study.

BACKGROUND: Biomarkers for predicting response to immune checkpoint inhibitors (ICI) are scarce and often lack external validation. This study provides a comprehensive investigation of pretreatment C-reactive protein (CRP) levels as well as its longitudinal trajectories as a marker of treatment response and disease outcome in patients with advanced non-small cell lung cancer (NSCLC) undergoing immunotherapy with anti PD-1 or anti PD-L1 agents. METHODS: We performed a retrospective bi-center study to assess the association between baseline CRP levels and anti PD-(L)1 treatment outcomes in the discovery cohort (n = 90), confirm these findings in an external validation cohort (n = 101) and explore the longitudinal evolution of CRP during anti PD-(L)1 treatment and the potential impact of dynamic CRP changes on treatment response and disease outcome in the discovery cohort. Joint models were implemented to evaluate the association of longitudinal CRP trajectories and progression risk. Primary treatment outcomes were progression-free survival (PFS) and overall survival (OS), while the objective response rate (ORR) was a secondary outcome, respectively. RESULTS: In the discovery cohort, elevated pretreatment CRP levels emerged as independent predictors of worse PFS (HR per doubling of baseline CRP = 1.37, 95% CI: 1.16-1.63, p < 0.0001), worse OS (HR per doubling of baseline CRP = 1.42, 95% CI: 1.18-1.71, p < 0.0001) and a lower ORR ((odds ratio (OR) of ORR per doubling of baseline CRP = 0.68, 95% CI: 0.51-0.92, p = 0.013)). In the validation cohort, pretreatment CRP could be fully confirmed as a predictor of PFS and OS, but not ORR. Elevated trajectories of CRP during anti PD-(L)1 treatment (adjusted HR per 10 mg/L increase in CRP = 1.22, 95% CI: 1.15-1.30, p < 0.0001), as well as a faster increases of CRP over time (HR per 10 mg/L/month faster increase in CRP levels = 13.26, 95% CI: 1.14-154.54, p = 0.039) were strong predictors of an elevated progression risk, whereas an early decline of CRP was significantly associated with a reduction in PFS risk (HR = 0.91, 95% CI: 0.83-0.99, p = 0.036), respectively. CONCLUSION: These findings support the concept that CRP should be further explored by future prospective studies as a simple non-invasive biomarker for assessing treatment benefit during anti PD-(L)1 treatment in advanced NSCLC.

Immune cell landscape in therapy-naïve squamous cell and adenocarcinomas of the lung.

Squamous cell and adenocarcinomas of the lung develop different mechanisms during carcinogenesis to evade attacks of the immune system. Besides the well-known check-point control programmed death 1 and its ligand, many more mechanisms, acting either tumoricidal or in favor of tumor progression, exist. Analysis of the immune cell profiles in resected tissues and bronchoalveolar lavage samples and correlation between them and with overall survival data was performed. In all tumor samples in this study, cells of the immune system expressed a tumor-cooperating phenotype. High numbers of regulatory T cells, or alternatively expression of Vista on lymphocytes was present. Tumoricidal dendritic cells were absent in tumor tissue, and barely present in bronchoalveolar lavage, whereas tumor-friendly monocytoid and plasmocytoid dendritic cells were seen in both. Alveolar macrophages were predominantly differentiated into tumor-cooperating M2 types, whereas tumoricidal M1 macrophages were absent or rare. The expression of PDL1 on tumor cells did not correlate with any other immune cells. Expression of PD1 on lymphocytes was frequently encountered. None of analyzed immune cells showed correlation with overall survival. Immune cells in bronchoalveolar lavage and tissue did not correlate. For the first time, a tissue-based analysis of different immune cells in squamous cell and adenocarcinomas of the lung is provided, trying to explain their potential role in tumor development and progression. Discordant numbers of cells with bronchoalveolar lavage are most probably due to the fact that bronchoalveolar lavage reflects the situation in the whole lung, where chronic obstructive lung disease and other conditions are present.

Cell-Free Plasma DNA-Guided Treatment With Osimertinib in Patients With Advanced EGFR-Mutated NSCLC.

INTRODUCTION: Osimertinib is standard treatment for patients with advanced EGFR T790M-mutated non-small-cell lung cancer who have been pre-treated with EGFR-tyrosine kinase inhibitors (TKIs). We studied whether cell-free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in the clinical routine. METHODS: From April 2015 to November 2016, we included 119 patients with advanced EGFR-mutated non-small-cell lung cancer who had progressed under treatment with an EGFR-TKI. The T790M mutation status was assessed in cell-free plasma DNA by droplet digital polymerase chain reaction in all patients and by tissue analyses in selected patients. RESULTS: T790M mutations were detected in 85 (93%) patients by analyses of cell-free plasma DNA and in 6 (7%) plasma-negative patients by tumor re-biopsy. Eighty-nine of 91 T790M-positive patients received osimertinib. Median progression-free survival (PFS) was 10.1 months (95% confidence interval [CI]: 8.1-12.1). Median survival was not reached and the 1-year survival was 64%. The response rate was 70% in T790M-positive patients (n = 91) in the intention-to-treat population. PFS trended to be shorter in patients with high T790M copy number (≥10 copies/mL) compared to those with low T790M copy number (<10 copies/mL) (hazard ratio for PFS = 1.72, 95% CI: 0.92-3.2, p = 0.09). A comparable trend was observed for overall survival (hazard ratio for overall survival = 2.16, 95% CI: 0.89-5.25, p = 0.09). No difference in response rate was observed based on T790M copy numbers. CONCLUSION: Plasma genotyping using digital polymerase chain reaction is clinically useful for the selection of patients who had progressed during first-line EGFR-TKI therapy for treatment with osimertinib.

ASCO update: lung cancer.

In the past few years there have been major changes in the treatment landscape in oncology; lung cancer is affected by those changes like almost no other solid tumor. The rise of further second- and third-line tyrosine kinase inhibitors offers sequential therapy for patients with mutated non-small-cell lung cancer. Immunotherapy has found its way into clinical routine and presents us with new challenges in managing side effects, evaluating treatment response and deciding on how long we treat our patients. The treatment algorithm of lung cancer has changed in the last month and further practice-changing trials are coming up, so treating lung cancer patients shows nowadays a more challenging perspective with the possibility of subsequently applied individual therapies. This article provides a brief overview of the highlights presented at the ASCO (American Society of Clinical Oncology) annual meeting this year in Chicago.

Frequency and clinical impact of preoperative circulating tumor cells in resectable non-metastatic lung adenocarcinomas.

OBJECTIVES: Despite successful surgery, 30-50% of patients with resectable non-small cell lung cancer develop tumor recurrence within 5 years of surgery. MATERIALS AND METHODS: In this prospective study, we performed CTC enumerations in 40 patients with non-metastatic lung adenocarcinoma (NMLA) using a size-based microfilter. Additionally, cfDNA isolated from plasma was analyzed in 35 out of 40 patients. RESULTS: CTCs were identified in 15 out of 40 patients (37.5%) with a range of 1-44 cells, whereas mutated cfDNA was only detected in 3 out of 35 patients (8.6%). Disease-free survival (DFS) was significantly associated with CTC positivity (log-rank p=0.025), grading (log-rank p=0.019), tumor stage (log-rank p=0.025) and lymph node status (log-rank p=0.029). Multivariate analysis, including tumor stage and grading, showed that CTC positivity (p=0.006), grading (0.039) and tumor stage (p=0.022) were independently associated with DFS. CONCLUSION: Our study found that microfilter-based CTC enumeration in NMLA patients is an independent predictor of worse DFS. The used NGS-based cfDNA characterization had limited sensitivity to be clinically informative in our study cohort. CTC assessment before surgery can thus identify NMLA patients at high risk of disease recurrence.

The elevated preoperative platelet to lymphocyte ratio predicts decreased time to recurrence in colon cancer patients.

BACKGROUND: Recent evidence indicates that tumor progression involves factors of systemic inflammation, such as platelets and lymphocytes. In this study, we investigated the prognostic relevance of the preoperative platelet to lymphocyte (P/L) ratio on time to recurrence (TTR) and overall survival (OS) in patients with stage II and III colon cancer (CC) who underwent curative resection. METHODS: In this retrospective study, 372 CC patients were included. Kaplan-Meier curves and multivariate Cox proportional models were calculated for TTR and OS. RESULTS: In univariate analysis, the elevated P/L ratio was significantly associated with decreased TTR (HR = 1.60, 95% CI = 1.02 to 2.51, P = .040) and remained significant in multivariate analysis (HR = 1.65, 95% CI = 1.05 to 2.58, P = .030), where HR and CI represent Hazard ratio and confidence interval, respectively. Patients with elevated P/L ratio showed a median TTR of 116 months. In contrast, patients with low P/L ratio had a median TTR of 132 months. In OS analysis, the elevated P/L ratio showed a trend toward decreased OS in univariate analysis (HR = 1.54, 95% CI = .95 to 2.48, P = .079). CONCLUSION: In this study, we identified the preoperative P/L ratio as a prognostic marker for TTR in stage II and III CC patients.

A functional germline variant in GLI1 implicates hedgehog signaling in clinical outcome of stage II and III colon carcinoma patients.

PURPOSE: Cumulating evidence indicates that germline variants in the Wnt, Notch, and Hedgehog pathways are involved in colon carcinoma progression and metastasis. We investigated germline polymorphisms in a comprehensive panel of Wnt, Notch, and Hedgehog pathway genes to predict time to recurrence (TTR) and overall survival in patients with stage II and III colon carcinoma. EXPERIMENTAL DESIGN: A total of 742 consecutively collected patients with stage II and III colon carcinoma were included in this retrospective study. Genomic DNA was analyzed for 18 germline polymorphisms in Wnt, Notch, and Hedgehog pathway genes (SFRP, DKK 2 and 3, AXIN2, APC, MYC, TCF7L2, NOTCH2, and GLI1) by TaqMan 5'-exonuclease assays. RESULTS: In univariate analysis, the homozygous mutant variant of GLI1 rs2228226 G>C was significantly associated with decreased TTR in a recessive genetic model after adjustment for multiple testing [HR = 2.35; confidence interval (95% CI), 1.48-3.74; P < 0.001] and remained significant in multivariate analysis including clinical stage, lymphovascular-, vascular-, and perineural-invasion (HR = 2.43; CI 95%, 1.52-3.87; P < 0.001). In subanalyses, the association was limited to patients with surgery alone (HR = 3.21; CI 95%, 1.59-6.49; P = 0.001), in contrast with patients with adjuvant chemotherapy (HR = 0.82; CI 95%, 0.35-1.95; P = 0.657). When the subgroup of patients with "high-risk" GLI1 rs2228226 C/C genotype was analyzed, no benefit of adjuvant 5-fluorouracil-based chemotherapy could be found. CONCLUSION: This is the first study identifying GLI1 rs2228226 G>C as an independent prognostic marker in patients with stage II and III colon carcinoma. Prospective studies are warranted to validate our findings.

The elevated pre-operative plasma fibrinogen level is an independent negative prognostic factor for cancer-specific, disease-free and overall survival in soft-tissue sarcoma patients.

BACKGROUND AND OBJECTIVES: Accumulating evidence indicates an important pathophysiological role of fibrinogen on tumor cell progression and metastases in different types of cancer. The aim of the present study was to evaluate the prognostic relevance of pre-operative fibrinogen levels on clinical outcome in a large cohort of STS patients. METHODS: Two hundred ninety-four consecutive STS patients were retrospectively evaluated. Cancer-specific survival (CSS), disease-free survival (DFS), and overall survival (OS) were assessed using the Kaplan-Meier curves and Cox regression models. Finally, we supplemented the well-established Kattan nomogram by the fibrinogen level and evaluated the gain of predictive accuracy of this novel nomogram by Harrell's concordance index (c-index). RESULTS: An elevated plasma fibrinogen level was significantly associated with established prognostic factors, including age, tumor grade, size, and depth (P<0.05). Furthermore, in multivariate analysis, increased fibrinogen levels were significantly associated with a poor outcome for CSS (HR=2.48; 95% CI=1.28-4.78; P=0.007), DFS (HR=2.00; 95% CI=1.11-3.60; P=0.021), and OS (HR=2.20; 95% CI=1.39-3.47; P<0.001). The estimated c-index was 0.747 using the original Kattan nomogram and 0.779 when the fibrinogen levels was added. CONCLUSION: The pre-operative plasma fibrinogen level may represent a strong and independent unfavorable prognostic factor for CSS, DFS and OS in STS patients.