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Background: Circulating tumor DNA (ctDNA) provides molecular information on tumor heterogeneity. Data regarding the predictive significance of ctDNA after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are limited. Thus, this study analyzed ctDNA during osimertinib administration as a second-line or greater setting to examine the association between EGFR mutation levels and clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC).Methods: Forty patients with EGFR T790M-positive NSCLC receiving osimertinib after prior EGFR-TKI treatment were enrolled. Plasma samples were obtained at osimertinib pretreatment, after 1 month of treatment, and at the time of progressive disease (PD). ctDNA analysis was performed using digital polymerase chain reaction.Results: The detection rate of copy numbers of exon 19 deletion, L858R, and T790M in plasma samples was significantly lower 1 month after osimertinib treatment than at pretreatment and significantly higher at PD than at 1 month, whereas that of C797S was significantly higher at PD than at 1 month. There was no statistically significant difference in the copy numbers of exon 19 deletion, L858R, T790M, and C797S between complete response or partial response and stable disease or PD.T790M detection at PD after osimertinib initiation was a significant independent prognostic factor for predicting worse prognosis, and the presence of major EGFR mutations at pretreatment and PD was closely associated with shorter survival after osimertinib initiation.Conclusion: Molecular testing based on ctDNA is useful for predicting outcomes of osimertinib treatment in T790M-positive NSCLC after previous EGFR-TKI treatment.

Background S‐1 monotherapy is effective and feasible for previously treated patients with advanced non‐small cell lung cancer (NSCLC). However, it is not clear whether its effectiveness and tolerability in elderly patients are equivalent to those in younger patients. Hence, this study aimed to evaluate the efficacy and feasibility of S‐1 monotherapy in elderly patients with NSCLC who had previously received other treatments. Methods We included 96 elderly patients (aged ≥75 years) with advanced NSCLC treated with S‐1 alone as a subsequent‐line treatment at 12 medical facilities between January 2005 and March 2018 in this study. The baseline characteristics of the patients, response to S‐1 monotherapy, and adverse events (AEs) were investigated, retrospectively. Results A total of 68 male and 28 female patients (median age, 78 [range: 75–86] years) were analyzed. In elderly patients who were treated with S‐1 monotherapy as a subsequent‐line treatment, the objective response rate, disease control rate, median progression‐free survival (PFS), and overall survival (OS) were 8.3%, 43.8%, 3.4 months, and 9.6 months, respectively. Observed AEs included anorexia, anemia, nausea, fatigue, reduced platelet count, and skin hyperpigmentation. Treatment‐related death was observed in one patient because of pneumonitis. In patients who experienced no progressive disease, subsequent‐line S‐1 alone was associated with longer PFS and OS. Conclusions S‐1 monotherapy is effective and feasible as a subsequent‐line treatment in elderly patients who were previously treated for NSCLC, and it produces results. S‐1 monotherapy could be one of the treatment choices for elderly patients with previously treated NSCLC., Kaplan–Meier analysis of (a) progression‐free survival (PFS) and (b) overall survival for the 96 patients in the study.

Background Lung cancer is the leading cause of cancer-related deaths. Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective for advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations, some patients experience little or no response. The Glasgow prognostic score (GPS) is an inflammation-related score based on C-reactive protein (CRP) and albumin concentrations, and has prognostic value in various cancer settings. This study aimed to evaluate whether GPS could predict response of NSCLC to EGFR-TKIs. Methods This retrospective multicenter study evaluated patients with NSCLC harboring EGFR mutations who received EGFR-TKI monotherapy from October 2006 to December 2016. GPS values were determined using CRP and albumin concentrations from before initiation of EGFR-TKIs. The Kaplan-Meier method and Cox proportional hazard models were used to evaluate progression-free survival (PFS) and overall survival (OS). Results In 214 patients, 141, 43, and two patients had GPS values of 0, 1, and 2, respectively. The GPS independently predicted the efficacy of EGFR-TKIs; good GPS (0-1) conferred significantly better PFS (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.38-0.96, P = 0.03) and OS (HR: 0.56, 95% CI: 0.33-0.96, P = 0.03). Multivariate analysis confirmed that a good GPS (0-1) independently predicted good PFS and OS among patients who had PS of 0-1. Good GPS (0-1) independently predicted good OS among patients receiving treatment in first-line settings. Conclusions The GPS independently predicted the efficacy of EGFR-TKIs for EGFR-mutated NSCLC; however, further studies are needed to validate our findings. Key points SIGNIFICANT FINDINGS OF THE STUDY: Glasgow prognostic score (GPS) independently predicted the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment for EGFR-mutated NSCLC. What this study adds The findings presented in this paper will help to identify patients who will be expected to experience limited or no response to EGFR-TKI treatment by using GPS.

Recent studies have indicated that afatinib is beneficial for patients with non‐small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations, while the effectiveness of afatinib rechallenge has not been fully defined. Here, we report a long‐term survival case of NSCLC harboring concomitant EGFR G719C and S768I mutations who received afatinib rechallenge followed by chemotherapy. The present case suggests that combined therapeutic strategies such as afatinib plus sequential chemotherapy would be beneficial based on appropriately timed rebiopsies from recurrent lesions. Key points Significant findings of the study and what this study adds A NSCLC patient carrying EGFR G719X/S768I mutations survived for a long period of time with afatinib rechallenge followed by chemotherapy. Combined therapeutic strategies should be considered based on rebiopsies in appropriate timing in NSCLC with uncommon EGFR mutations.

Immune checkpoint inhibitors (ICIs) are an effective subsequent-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, it remains unclear whether the efficacy and safety of subsequent-line ICI monotherapy in elderly patients (aged ≥ 75 years) are similar to that in non-elderly patients. Therefore, we aimed to investigate the efficacy and safety of ICI monotherapy in pretreated elderly patients with NSCLC. Between January 2016 and February 2018, 131 elderly patients with advanced NSCLC who received subsequent-line ICI monotherapy at 13 Japanese institutions were enrolled in this study. Baseline characteristics, the efficacy of ICI treatment, and adverse events were evaluated. Ninety-eight men and 33 women (median age 77 [range 75–87] years) were enrolled. Among those who received subsequent-line ICI monotherapy, the overall response, disease control rates, median progression-free survival (PFS), and overall survival (OS) were 27.4%, 61.8%, 4.5 months, and 16.0 months, respectively. Adverse events such as anorexia, fatigue, pneumonitis, and hypothyroidism were observed. There were two treatment-related deaths due to pneumonitis and thrombocytopenia. Subsequent-line ICI monotherapy in patients with good performance status (PS), receiving steroids for immune-related adverse events (irAEs), and exhibiting partial response (PR) was associated with improved PFS, as well as OS in patients with good PS and PR. Subsequent-line ICI monotherapy in elderly patients, with previously treated NSCLC, was effective, safe and showed outcomes equivalent to those in non-elderly patients. Immunotherapy provides a survival benefit for elderly patients, who exhibit its efficacy and a favorable general condition.

Background/aim The efficacy of the combination of amrubicin and bevacizumab against advanced non small-cell lung cancer (NSCLC), as a second or third-line treatment, was evaluated. Patients and methods Amrubicin was administered for 3 days to patients with previously treated advanced NSCLC, whereas bevacizumab was administered on day 1 of each cycle; this regimen was repeated every 3 weeks. Results Among the 16 patients, an overall response rate of 12.5% (for two patients) was achieved, and the overall disease control rate was 93.7%. Progression free survival and overall survival were 8.5 and 16.6 months, respectively. Grade 3 or 4 haematological toxicities were leukopenia, neutropenia, and febrile neutropenia. Grade 3 proteinuria and infection were the non haematological adverse events. Conclusion The combination of amrubicin and bevacizumab is a promising regimen in the second or third-line treatment for advanced non-squamous NSCLC; however, physicians must recognise the risk of proteinuria related with this regimen.

Lung cancer is the leading cause of cancer-related death throughout the world. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers, and lung adenocarcinoma (LUAD) is the major subtype of NSCLC.

Coronavirus disease 2019 (COVID-19) has become a global pandemic since its discovery in December 2019, and as the disease continues to evolve, varying complications associated with it continue to arise. In this regard, computed tomography has played an extremely important role in the diagnosis and evaluation of COVID-19 pneumonia and its complications. We encountered a case of a male patient with neurofibromatosis (type I) who developed concurrent pneumothorax and pleural effusion during his recovery period from severe COVID-19 pneumonia. Pulmonary fibrosis and emphysema were also confirmed. Furthermore, an eosinophil pleural effusion appeared and was prolonged during the healing process of COVID-19. This clinical presentation suggests that fibrosis and emphysema formation due to neurofibromatosis may have caused pneumothorax and pleural effusion.

Background/aim It remains unclear which chemotherapeutic regimens are better for the addition of bevacizumab. We conducted an exploratory randomized phase II trial comparing first-line S-1 plus cisplatin with bevacizumab and pemetrexed plus cisplatin with bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC). Patients and methods Chemotherapy-naive patients received S-1 (80 mg/m2) from day 1 to day 14 plus cisplatin (80 mg/m2) on day 1 with bevacizumab (15 mg/kg) on day 1, followed by maintenance with bevacizumab plus S-1 (SCB) on day 1 every 3 weeks and pemetrexed (500 mg/m2) on day 1 plus cisplatin (75 mg/m2) on day 1 with bevacizumab (15 mg/kg) on day 1 followed by maintenance bevacizumab plus pemetrexed (PCB) on day 1 every 3 weeks. The expression of thymidylate synthase (TS) was analyzed using immunohistochemistry. Results Forty-eight patients were enrolled in this study, and eligible patients were randomly assigned at 1:1 ratio to receive SCB (n=24) or PCB (n=24). The median number of chemotherapy and maintenance therapy for SCB and PCB was 4 (range, 1-6 cycles) and 4 (range, 2-6 cycles), and 5 (range, 0-39 cycles) and 5 (range, 0-28 cycles), respectively. The overall response rate (ORR) for PCB and SCB were 54.2% and 83.3%, respectively (p=0.06). The median progression-free survival (PFS) and overall survival (OS) for PCB and SCB were 406 and 351 days, (p=0.96), and 678 and 1190 days, respectively (p=0.23). The mild adverse events were observed in both regimens. TS expression was more predictive of the chemotherapeutic response in SCB compared to PCB, but not for PFS. Conclusion The combination regimen of SCB was identified as having a similar activity and tolerability to that of PCB in patients with advanced non-squamous NSCLC.

A 69-year-old woman was diagnosed with sarcoidosis, which was not treated with corticosteroid therapy. Her levels of angiotensin converting enzyme decreased significantly over 4 years and a mass lesion was detected near the lower part of her left main bronchus, and diagnosed as small cell lung cancer (SCLC). Treatment of the SCLC with a series of chemotherapeutic agents produced excellent results. The pulmonary sarcoidosis did not show any deterioration despite the frequent use of amrubicin, which is known to be a cause of interstitial pneumonia. This is a case report of SCLC complicated with sarcoidosis in a stage of spontaneous remission, possibly suggesting an association between sarcoidosis and tumor immunity, since recent reports have suggested that immune checkpoint inhibitors might be involved in the development of sarcoidosis.

Periostin, an extracellular matrix molecule, is associated with idiopathic pulmonary fibrosis (IPF). It is known that the frequency of familial IPF (FIPF) ranges from 0.5% to 2.2% among IPF cases. However, the relationship between periostin and FIPF has not been previously described. We report the first case of periostin accumulation in the lungs of a patient with an acute exacerbation of FIPF. A 72-year-old woman, diagnosed with FIPF, had been followed up for 5 years. The patient experienced increased dyspnea within a 1-month period and was referred to our hospital. The patient was hypoxic, and chest computed tomography showed rapidly expanding bilateral reticular shadows. Despite pulse-steroid and intravenous-cyclophosphamide therapy, the patient died 25 days after admission. On admission, serum periostin levels were not significantly elevated, while serum fibrotic marker levels were elevated. Immunohistochemical analysis of the lungs on autopsy showed marked accumulation of periostin in the active fibrotic lesions, whereas intact and burned-out areas did not show significant expression of periostin. This case might provide insight into the role of periostin in acute exacerbation of IPF.

A 66-year-old man had been treated with prednisolone for eosinophilic pneumonia for 8 years. His slowly progressing cough and dyspnea were accompanied by elevated levels of fibrotic serological markers and an increased reticular shadow on chest computed tomography images. The patient had recently tested positive for anti-EJ antibodies, a type of anti-aminoacyl-tRNA synthetase antibody; therefore, we diagnosed him with an exacerbation of interstitial pneumonia due to anti-synthetase syndrome (ASS). He was treated with tacrolimus and an increased prednisolone dosage. We herein present the first reported case of eosinophilic pneumonia preceding anti-EJ antibody-positive ASS.

Simple Summary v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is the most common driver in NSCLC, and targeting oncogenic KRAS is a major challenge in the treatment of non-small-cell lung cancer (NSCLC). While several covalent KRAS G12C inhibitors have emerged as a novel anti-KRAS therapy, the development of combined therapies involving the targeting of oncogenic KRAS plus other targeted drugs is still required given the vast heterogeneity of KRAS-mutated tumors. In this review, we summarize the biological and immunological characteristics of oncogenic KRAS-driven NSCLC and the preclinical and clinical evidence for mutant KRAS-targeted therapies. We also discuss the mechanisms of resistance to KRAS G12C inhibitors and possible therapeutic strategies to overcome this drug resistance. Abstract Recent advances in molecular biology and the resultant identification of driver oncogenes have achieved major progress in precision medicine for non-small-cell lung cancer (NSCLC). v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is the most common driver in NSCLC, and targeting KRAS is considerably important. The recent discovery of covalent KRAS G12C inhibitors offers hope for improving the prognosis of NSCLC patients, but the development of combination therapies corresponding to tumor characteristics is still required given the vast heterogeneity of KRAS-mutated NSCLC. In this review, we summarize the current understanding of KRAS mutations regarding the involvement of malignant transformation and describe the preclinical and clinical evidence for targeting KRAS-mutated NSCLC. We also discuss the mechanisms of resistance to KRAS G12C inhibitors and possible combination treatment strategies to overcome this drug resistance.

Objectives Epidermal growth factor receptor (EGFR) mutation testing is a companion diagnostic to determine eligibility for treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). Recently, plasma-based EGFR testing by digital polymerase chain reaction (dPCR), which enables accurate quantification of target DNA, has shown promise as a minimally invasive diagnostic. Here, we aimed to evaluate the accuracy of a plasma-based EGFR mutation test developed using chip-based dPCR-based detection of 3 EGFR mutations (exon 19 deletions, L858R in exon 21, and T790M in exon 20). Materials and methods Forty-nine patients with NSCLC harboring EGFR-activating mutations were enrolled, and circulating free DNAs (cfDNAs) were extracted from the plasma of 21 and 28 patients before treatment and after progression following EGFR-TKI treatment, respectively. Results Using reference genomic DNA containing each mutation, the detection limit of each assay was determined to be 0.1%. The sensitivity and specificity of detecting exon 19 deletions and L858R mutations, calculated by comparing the mutation status in the corresponding tumors, were 70.6% and 93.3%, and 66.7% and 100%, respectively, showing similar results compared with previous studies. T790M was detected in 43% of 28 cfDNAs after progression with EGFR-TKI treatment, but in no cfDNAs before the start of the treatment. Conclusion This chip-based dPCR assay can facilitate detection of EGFR mutations in cfDNA as a minimally invasive method in clinical settings.

There is no standard chemotherapy for pulmonary large-cell neuroendocrine carcinoma (LCNEC) and this type of cancer is difficult to diagnose using biopsy specimens. At the Shizuoka Cancer Center, when small biopsy specimens are used, they are diagnosed as high-grade non-small-cell neuroendocrine carcinoma (HNSCNEC) and the patients are treated according to the small-cell lung cancer (SCLC) guidelines. Amrubicin is an effective second-line treatment for patients with SCLC, although it remains unclear whether amrubicin monotherapy is effective for patients with LCNEC or HNSCNEC. Between September, 2004 and December, 2013, 18 patients with advanced LCNEC or HNSCNEC received amrubicin monotherapy in the second-line setting. The efficacy and toxicity of this treatment were retrospectively assessed. A total of 6 patients had LCNEC and 12 patients had HNSCNEC. The patients included 13 men, and the median age was 66 years (range, 57-82 years). A total of 16 patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. All the patients had received platinum-based chemotherapy as first-line treatment, and the median number of amrubicin cycles per patient was 4 (range, 1-9). The overall response rate was 11.1%. The median progression-free and overall survival were 4.0 and 9.1 months, respectively. Grade 3 or 4 neutropenia was observed in 44% of the patients, and grade 3 febrile neutropenia occurred in 17% of the patients. One patient developed pneumonia and succumbed to the disease. Non-hematological toxicities were generally mild and manageable. Therefore, the efficacy of amrubicin in the second-line setting for patients with LCNEC or HNSCNEC is limited. Development of new drugs and/or treatment strategies is warranted.

Although docetaxel plus ramucirumab has shown superior treatment efficacy over docetaxel monotherapy for patients with non-small cell lung cancer (NSCLC), the high rate of febrile neutropenia (FN) presents a clinical problem. This study aimed to validate the primary prophylactic use of pegfilgrastim with docetaxel and ramucirumab treatment in Japanese patients with NSCLC. Patients with NSCLC with progression after at least one round of chemotherapy were enrolled and administered docetaxel (60 mg/m2) plus ramucirumab (10 mg/kg) intravenously on day 1, followed by pegylated-granulocyte colony-stimulating factor (3.6 mg) on day 2 of a 21-day treatment cycle. The primary study endpoint was the percentage of patients who developed FN. Secondary endpoints included overall survival, progression-free survival, overall response rate, and safety. Overall, 20 patients (15 men and 5 women) were enrolled, of whom one developed FN, resulting in an overall FN rate of 5%. The response and disease control rates were 40% and 85%, respectively. The median progression-free survival was 6.6 (95% confidence interval [CI], 0.5-NR) months. The median overall survival was 18.4 (95% CI, 2.2–11.0) months. Six patients aged over 75 years were included in this study, and although most adverse events were durable, ramucirumab-associated adverse events occurred more frequently in these patients. We observed a 5% FN rate using primary prophylactic pegylated-granulocyte colony-stimulating factor with docetaxel plus ramucirumab in Japanese patients with NSCLC. While most adverse events were durable, elderly patients should be closely monitored.

Objectives Positron emission tomography (PET) using 2-deoxy-2-[18F] fluoro-D-glucose (18F-FDG) is a clinically useful modality for cancer evaluation. The mechanism of 18F-FDG uptake within cancer cells involves the glucose transporter 1 (GLUT1) and hypoxia-inducible factor-1 α (HIF-1α). Although recent research has shown its clinical efficacy in small-cell lung cancer (SCLC), no suitable biomarker has been identified. We conducted a clinicopathological study to examine the relationship between tumor immunity and 18F-FDG uptake in patients with SCLC. Materials and methods Tumor sections were stained by immunohistochemistry for GLUT1, HIF-1α, PD-L1, CD4, CD8, and Foxp3. The relationship between clinicopathological features and 18F-FDG uptake was analyzed. Student’s t-test, χ2 test, non-parametric Spearman’s rank test, and Kaplan–Meier method were used to evaluate associations between the variables. Results A total of 98 patients 78 men and 20 women who underwent 18F-FDG PET, were enrolled in this study. PD-L1 was expressed in 36.7% (36/98) of all patients; this was significantly associated with GLUT1 expression (p = 0.04). The accumulation of 18F-FDG was significantly higher in patients with low CD8 and CD4 TILs than in those with high TILs (p = 0.03 and p = 0.01, respectively). The uptake of 18F-FDG was not significantly associated with the expression of either Foxp3 or PD-L1. Multivariate analysis demonstrated that advanced stage, poor ECOG-PS, and high SUVmax were independent predictors of poor OS. Among patients with limited-stage disease, multivariate analysis confirmed high PD-L1 expression and a high SUVmax to be independent predictors of poor OS. However, only ECOG-PS was found to be an independent predictor of poor OS among patients with extensive-stage tumors. Conclusion High SUVmax on 18F-FDG-PET is correlated with low expression of CD8(+) and CD4(+) TILs, but is an independent prognostic factor for OS, particularly in those with limited disease. Further studies are warranted to validate our findings.

Despite the high frequency of KRAS mutations in non-small cell lung cancer (NSCLC), therapeutic modalities targeting KRAS-mutated NSCLC have not been established. Based on our previous findings that mutant KRAS knockdown sensitized NSCLC cells to a p38 inhibitor, the growth-inhibitory effect of dual MEK and p38 inhibition on tumor growth in NSCLC cells harboring KRAS mutations was investigated. In KRAS-mutated NSCLC cells, the MEK inhibitor, selumetinib, inhibited cell growth in a dose-dependent manner, and its growth-inhibitory effect was enhanced by combined treatment with the p38 inhibitor LY2228820. Similarly, another pair of MEK and p38 inhibitors also exhibited antitumor activity. Small interfering RNAs (siRNAs) against MAPK14, which encodes p38α MAPK, enhanced the growth-inhibitory effect of the MEK inhibitors in NSCLC cells with KRAS mutations. Notably, MEK inhibitors reduced p38 expression levels but increased p38 phosphorylation levels, resulting in sensitization to p38 inhibitors in KRAS-mutated NSCLC cells. These results provide evidence that dual MEK and p38 inhibition could be a potent therapeutic strategy against oncogenic KRAS-driven NSCLC.

Background/aim No definitive biomarker exists for predicting treatment efficacy or response to therapy with antibody to programmed cell death-1 (PD1) for patients with advanced non-small cell lung cancer (NSCLC). Hence, we investigated whether the Glasgow prognostic score (GPS) predicted anti-PD1 treatment response for advanced NSCLC. Patients and methods This study retrospectively identified 47 patients with NSCLC treated with anti-PD1 and assessed the prognostic value of the GPS. The GPS was calculated using C-reactive protein and albumin concentrations 1 month after starting anti-PD1 treatment. Kaplan-Meier method and Cox proportional hazard models were used to examine differences in progression-free (PFS) and overall (OS) survival, and clinical response. Results The post-treatment GPS independently predicted anti-PD1 treatment efficacy, as a good post-treatment GPS (GPS 0-1) was significantly associated with improved PFS. Intra-treatment GPS change was associated with clinical response. Conclusion The post-treatment GPS independently predicted efficacy of anti-PD1 treatment for NSCLC.

Despite the high frequency of KRAS mutations in non-small cell lung cancer (NSCLC), therapeutic modalities targeting KRAS-mutated NSCLC have not been established. Based on our previous findings that mutant KRAS knockdown sensitized NSCLC cells to a p38 inhibitor, the growth-inhibitory effect of dual MEK and p38 inhibition on tumor growth in NSCLC cells harboring KRAS mutations was investigated. In KRAS-mutated NSCLC cells, the MEK inhibitor, selumetinib, inhibited cell growth in a dose-dependent manner, and its growth-inhibitory effect was enhanced by combined treatment with the p38 inhibitor LY2228820. Similarly, another pair of MEK and p38 inhibitors also exhibited antitumor activity. Small interfering RNAs (siRNAs) against MAPK14, which encodes p38α MAPK, enhanced the growth-inhibitory effect of the MEK inhibitors in NSCLC cells with KRAS mutations. Notably, MEK inhibitors reduced p38 expression levels but increased p38 phosphorylation levels, resulting in sensitization to p38 inhibitors in KRAS-mutated NSCLC cells. These results provide evidence that dual MEK and p38 inhibition could be a potent therapeutic strategy against oncogenic KRAS-driven NSCLC.

Background. The effects of first-line chemoradiotherapy on overall survival (OS) may be confounded by subsequent lines of therapy in patients with limited-stage disease small cell lung cancer (LD-SCLC). Therefore, we aimed to determine the relationships between progression-free survival (PFS), post-progression survival (PPS) and OS after first-line chemoradiotherapy in LD-SCLC patients. Patients and methods. We retrospectively analyzed 71 LD-SCLC patients with performance status (PS) 0-2 who received first-line chemoradiotherapy and had disease recurrence between September 2002 and March 2013 at Shizuoka Cancer Center (Shizuoka, Japan). We determined the correlation between PFS and OS and between PPS and OS at the individual level. In addition, we performed univariate and multivariate analyses to identify significant prognostic factors of PPS. Results. OS is more strongly correlated with PPS (Spearman’s r = 0.86, R 2 = 0.72, p < 0.05) than PFS (Spearman’s r = 0.46, R 2 = 0.38, p < 0.05). In addition, the response to second-line treatments, the presence of distant metastases at recurrence and the number of additional regimens after first-line chemoradiotherapy were significant independent prognostic factors for PPS. Conclusions. PPS has more impact on OS than PFS in recurrent LD-SCLC patients with good PS at beginning of the treatment. Moreover, treatments administered after first-line chemoradiotherapy may affect their OS. However, larger multicenter studies are needed to validate these findings.

Objectives 2-Deoxy-2-[fluorine-18] fluoro- d -glucose with positron emission tomography (18F-FDG-PET) is a clinically useful tool for cancer evaluation. 18F-FDG accumulation in tumor cells is known to be correlated with the presence of glucose transporter 1 (GLUT1) and hypoxia-inducible factor-1α (HIF-1α). Although anti-programmed death-1 (PD-1) antibody treatments have been approved, no suitable predictor of significant responders has been identified. Based on the existing information, we investigated the relationship between tumor immunity (including PD-L1) and 18F-FDG uptake in patients with surgically resected pulmonary squamous-cell carcinoma (SQC). Materials and methods This study included 167 patients (153 men and 14 women) with SQC who underwent 18F-FDG PET. Tumor sections were stained by immunohistochemistry for GLUT1, HIF-1α, PD-L1, CD4, CD8, and Foxp3. The relationship between clinicopathological features and 18F-FDG uptake was analyzed. Student’s t-test, the χ2 test, non-parametric Spearman’s rank test and the Kaplan–Meier method were used to show associations between variables. Results The rate of positive PD-L1 expression was 79% (132/167), and PD-L1 expression was significantly associated with GLUT1 (P Conclusion High SUVmax on 18F-FDG-PET is associated with PD-L1 expression but is an independent prognostic factor for OS in our population of surgically resected pulmonary squamous-cell carcinoma.

Mutant KRAS and BRAF are important oncogenic drivers in non-small cell lung cancer (NSCLC), however, effective treatment strategies for most of these mutants have not been established. Immuno-oncology clinical trials have shown promising results of anti-programmed death 1 (PD-1) antibodies for a subset of NSCLC patients and tumor expression of programmed-death ligand 1 (PD-L1) is regarded as a predictive marker for anti-PD-1 therapy. We found that CD274 mRNA and PD-L1 protein expression were reduced in NSCLC lines by small interfering RNAs (siRNAs) targeting mutant KRAS, but not wild-type KRAS, and also by pharmacologic inhibitors of MEK and ERK. In addition, there was a positive correlation between CD274 expression and KRAS expression in NSCLC lines, and analyses of The Cancer Genome Atlas (TCGA) database revealed that NSCLCs with high KRAS expression exhibited higher levels of CD274 compared to the tumors with low KRAS expression among KRAS-mutant NSCLCs. Similarly, siRNA-mediated BRAF knockdown and inhibitors of BRAF and MEK reduced PD-L1 expression in BRAF-mutant NSCLC cells, suggesting that PD-L1 expression was also upregulated by oncogenic BRAF. Mechanistically, these results suggest that oncogenic KRAS and BRAF induce PD-L1 overexpression in NSCLCs by activation of the MEK-ERK pathway. For clinical translation, our results suggest that: 1. in NSCLCs the combination of KRAS and PD-L1 overexpression could be a surrogate predictive marker for anti-PD-1 treatment; and 2. that since the goal of checkpoint inhibitor immuno-oncology therapy is to inhibit the PD-L1 axis, that a combination of anti-PD-1 and targeted therapy to inhibit the MEK-ERK pathway could be beneficial. Citation Format: Yosuke Miura, Noriaki Sunaga, Pinjie Bao, Luc Girard, Yusuke Tsukagoshi, Tomomi Masuda, Norimitsu Kasahara, Reiko Sakurai, Kyoichi Kaira, Takeshi Hisada, John Minna, Masanobu Yamada. PD-L1 overexpression induced by oncogenic KRAS and BRAF mutations through MAPK pathway activation in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5740.

e24138Background: 2-Deoxy-2-[fluorine-18] fluoro-D-glucose (18F-FDG) positron emission tomography (PET) is a useful modality for the assessment of tumor glucose metabolism by up-regulation by hypox...

Background: EGFR mutation testing is important in the treatment decision for advanced non-small cell lung cancer (NSCLC). Because T790M mutation in exon 20 is associated with approximately 50% of cases resistant to treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), the importance of re-biopsy for detecting T790M mutation during EGFR-TKI therapy is increasing. Circulating tumor DNA (ctDNA) is recognized as a promising target of minimally invasive diagnosis. Digital polymerase chain reaction (dPCR) is a new PCR technology for accurate quantification of the copy number of target molecules from low-input DNA. This study aimed to develop a blood-based EGFR mutation analysis in patients with advanced NSCLC by using a chip-based dPCR system that enables easy handling at a moderate costs. Methods: From October 2013 to March 2014, 49 patients with NSCLC harboring EGFR-activating mutations detected with the Scorpion ARMS method were enrolled in this study. ctDNA samples were extracted from plasma samples of 21 and 28 patients before treatment and after progression with EGFR-TKI, respectively. dPCR was performed on the QuantStudio 3D (QS3D) Digital PCR System (Life Technologies) by using 20 ng ctDNA, TaqMan probes for three EGFR mutations (exon 19 deletion, L858R in exon 21, and T790M in exon 20), and QS3D Digital PCR 20K Chips (2 chips per assay), according to the manufacturer's instructions. The performance of the dPCR assay was assessed by using HDx Reference Standards (Horizon) containing each mutant sequence serially diluted with that containing wild-type EGFR sequence. Results: Mutation of 0.1% was successfully detected in the dPCR assay for the three EGFR mutations. The median copy numbers of the EGFR mutation-positive samples were 2.9 copies (range, 0.3-84.2) for exon 19 deletion, 5.1 copies (0.6-742.1) for L858R in exon 21, and 1.4 copies (0.6-36.9) for T790M in exon 20. The sensitivity and specificity of each dPCR assay calculated by comparison with corresponding tumor samples were 61.8% (21/34) and 93.3% (14/15) for exon 19 deletion, and 66.7% (10/15) and 100% (34/34) for L858R, respectively. The T790M mutations were detected in 43% (12/28) of the ctDNA samples after progression with EGFR-TKIs therapy but in none of the samples before treatment with EGFR-TKIs. Among the 12 patients with NSCLC harboring T790M mutation in ctDNA, T790M mutations were detected in 5 of the 11 patients who underwent re-biopsy. Conclusions: This system showed similar performance to other dPCR assays used in previous studies (sensitivity: 66.6-92.0% and specificity: 95.7-100%). These results indicate the possibility that EGFR mutation testing with ctDNA using the chip-based dPCR for easy handling at a moderate costs is useful as a minimally invasive monitoring method in clinical settings. Citation Format: Norimitsu Kasahara, Hirotsugu Kenmotsu, Masakuni Serizawa, Rina Umehara, Akira Ono, Kazushige Wakuda, Shota Omori, Kazuhisa Nakashima, Tetsuhiko Taira, Tateaki Naito, Haruyasu Murakami, Noriaki Sunaga, Yasuhiro Koh, Keita Mori, Masahiro Endo, Takashi Nakajima, Masanobu Yamada, Masatoshi Kusuhara, Toshiaki Takahashi. Plasma epidermal growth factor receptor mutation (EGFR) testing in advanced non-small-cell lung cancer patients harboring EGFR mutations by chip-based digital PCR system. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2248.