Hibiki Udagawa

Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung

Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations. Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non–small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases). Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%–100%). Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies. Clin Cancer Res; 23(3); 757–65. ©2016 AACR.

Impact of denosumab use on the survival of untreated non-squamous non-small cell lung cancer patients with bone metastases

PurposeDenosumab reduces the incidence of skeletal-related events (SREs) in solid tumor patients with bone metastases (BM). However, there have been no detailed reports of the efficacy of denosumab in untreated non-squamous non-small cell lung cancer (NSCLC) patients with BM.MethodsThe medical records of patients with untreated non-squamous NSCLC and BM at diagnosis at our institution were reviewed retrospectively. The overall survival (OS) and the time to SREs were analyzed according to the treatment for the BM.ResultsOf the total of 149 patients who were eligible, 52 had received denosumab (Dmab group), 51 had received zoledronic acid (ZA group), and 46 had received no treatment (No-Tx group) for the BM. The frequencies of prior SREs were higher in the Dmab group and ZA group than in the No-Tx group (44, 41 and 22%, respectively); however, there were no significant differences in any of the other clinicopathological characteristics examined among the three groups. The median OS in the Dmab group, ZA group and No-Tx group were 21.4 months, 12.7 months and 10.5 months, respectively; the OS was significantly longer in the Dmab group than in the ZA group (P < 0.01). Results of multivariate analysis revealed that denosumab treatment was significantly associated with a more favorable survival [hazard ratio, 0.500; 95% CI 0.332–0.741; P < 0.01]. No significant difference in the time to SREs was observed among the three groups.ConclusionsOur results suggest that treatment with denosumab may improve the overall survival of non-squamous NSCLC patients with BM.

CD200-positive cancer associated fibroblasts augment the sensitivity of Epidermal Growth Factor Receptor mutation-positive lung adenocarcinomas to EGFR Tyrosine kinase inhibitors

Cancer associated fibroblasts (CAFs) play important roles in the chemotherapeutic process, especially through influencing the resistance of tumor cells to molecular targeted therapy. Here we report the existence of a special subpopulation of patient-specific-CAFs that augment the sensitivity of EGFR gene mutation-positive lung cancer to the EGFR-tyrosine kinase inhibitor (EGFR-TKI), gefitinib. When cocultured with EGFR mutation positive lung cancer cells, these CAFs increased the apoptic effect of gefitinib on cancer cells, whereas, in the absence of gefitinib, they did not affect cancer cell viability. The assay using different single cell-derived clones demonstrated that the aforementioned sensitizing ability is clone-specific. Microarray analysis revealed that CD200 was expressed at much higher levels in this CAFs. Knocking down of CD200 expression deprived CAFs of their sensitizing potential, suggesting that CD200 is the functional molecule responsible for the effect. Immunohistochemical analysis of samples from patients receiving postoperative gefitinib treatment revealed that the individuals whose resected lung adenocarcinomas contained CD200-positive CAFs tended to have longer progression free survival of gefitinib when they recurred after surgery. These results suggest that CD200-positive CAFs can augment the sensitivity to EGFR-TKIs and may possess far reaching applications in the therapeutic use of EGFR-TKIs.

Metabolic determinants of sensitivity to phosphatidylinositol 3-kinase pathway inhibitor in small-cell lung carcinoma

Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here, we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. Substantial phosphatidyl lipid analysis revealed that a specific phosphatidylinositol (3,4,5)-trisphosphate (PIP3) subspecies lipid product PIP3 (38:4) is predictive in assessing sensitivity to PI3K/mTOR dual inhibitor. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine, which are characteristic of SCLC biology, lead to resistance to PI3K pathway inhibition. In addition, the levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1, a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Moreover, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the resistance mechanism of PI3K pathway inhibitors is mediated by the activation of the purine salvage pathway, supplying purine resource to nucleotide biosynthesis. Metabolomics is a powerful approach for finding novel therapeutic biomarkers in SCLC treatment.Significance: These findings identify features that determine sensitivity of SCLC to PI3K pathway inhibition and support metabolomics as a tool for finding novel therapeutic biomarkers. Cancer Res; 78(9); 2179-90. ©2018 AACR.

Impact of prophylactic cranial irradiation on pattern of brain metastases as a first recurrence site for limited-disease small-cell lung cancer

Abstract This study sought to evaluate the impact of prophylactic cranial irradiation (PCI) on the pattern of brain recurrence after radical treatment in patients with limited-disease small-cell lung cancer (LD-SCLC). Patients treated with radiotherapy and chemotherapy between January 2006 and December 2014 at a single institution were retrospectively examined. Radiotherapy was performed using accelerated hyperfractionated radiotherapy (twice daily, 45 Gy in 30 fractions) or conventional fractionated radiotherapy (once daily, 50 Gy in 25 fractions). The chemotherapy regimen consisted of intravenous platinum–etoposide. A total of 162 patients were included and the median follow-up duration was 38 months. Ninety-three patients underwent PCI, and the 3-year overall survival (OS) rates were 14% among patients without PCI and 41% among those with PCI (P < 0.001). The frequency of brain metastases as a first recurrence site (BMFR) was significantly lower among patients who underwent PCI, compared with those who did not (P = 0.002). The median time to the l of BMFR was significantly shorter among patients without PCI than among those with PCI (P = 0.012). In addition, 68% of the BMFR patients who did not undergo PCI exhibited five or more lesions, while only 12% of BMFR patients who did undergo PCI exhibited five or more lesions (P < 0.001). PCI had a significant positive impact on patient prognosis after radical treatment for LD-SCLC, and the difference in the number of, and time to the appearance of, BMFR between patients treated with PCI and those treated without PCI might affect the clinical outcomes.

Salvage chemoradiotherapy with cisplatin and vinorelbine for postoperative locoregional recurrence of non-small cell lung cancer

Abstract Although a few investigators have demonstrated the effect of concurrent chemoradiotherapy (CRT) for postoperative recurrent non-small cell lung cancer (NSCLC), the outcome of this treatment remains unclear. The aim of this study was to elucidate the efficacy and tolerability of concurrent CRT with cisplatin (CDDP) and vinorelbine (VNR) in patients with postoperative locoregional recurrent NSCLC. A total of 40 patients who had received concurrent CRT with CDDP and VNR between January 1999 and December 2014 were retrospectively analyzed. Patients were treated with CDDP (80 mg/m2 on day 1) and VNR (20 mg/m2 on days 1 and 8) every 4 weeks. Radiotherapy was administered concurrently during cycle 1. The delivered x-ray radiation dose was 60 Gy in all 37 patients who received x-ray radiotherapy; 3 patients received proton beam radiation (66 Gy [RBE] in 1 patient and 60 Gy [RBE] in 2 patients). The objective response rate was 85% (95% confidence interval [CI], 70.9%–92.9%). The median progression-free survival was 20.3 months (95% CI, 12.9 months–not reached). The 2-year survival rate was 78.9% (95% CI, 63.0%–89.1%). The most common grade ≥3 toxicity was neutropenia (18%). No grade ≥3 radiation pneumonitis and no treatment-related deaths were observed. Our study revealed that concurrent CRT with CDDP and VNR was active and safe for patients with postoperative locoregional recurrent NSCLC. Salvage CRT for postoperative locoregional recurrent NSCLC might be a promising treatment for selected patients.

O2-7-4Association between immune-related adverse events and efficacy of nivolumab in advanced non-small cell lung cancer

events, nivolumab-induced pneumonitis, which infrequently develops but sometimes results in a fatal outcome, requires an early detection and prompt response. The purpose of this study was to understand the pathogenesis of nivolumab-induced pneumonitis, leading to avoiding its onset and increase in severity. Patients and Methods: The subjects were patients with malignant melanoma (n1⁄4 2) and non-small cell lung cancer (NSCLC) (n1⁄4 2), all of whom developed nivolumabinduced pneumonitis in Tokyo Medical University Hachioji Medical Center. We retrospectively analyzed clinicopathological characteristics of these patients from the medical records.

Molecular profiling-based prognostic prediction of patients with advanced small-cell lung cancer.

8560Background: Genetic alterations such as inactivating mutations in TP53 and RB1, gene amplifications of the MYC family members and genetic alterations in the PI3K/AKT/mTOR pathway were observed ...