Large-scale nationwide genomic screening system for small cell lung cancer in Japan (LC-SCRUM-Japan).

8559 Background: A variety of genetic analyses have been performed in small cell lung cancer (SCLC), however the clinical relevance of them remains unclear. We prospectively analyzed clinical samples of small-cell lung cancer using a nationwide genomic screening project (LC-SCRUM-Japan). Methods: Submitted tumor samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 (ver.1) or 161 (ver.3) cancer-related genes. Results: From July 2015 to January 2019, 707 SCLC patients had been enrolled. The median age was 68 years. 77% were male and 94% were smokers. Among 588 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 426 (72%) /194 (33%) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 21 (4%) /30 (5%) /9 (2%) of cases, respectively. This NGS analysis also showed that 32 (5%) of cases had well-known genetic alterations in receptor tyrosine kinase genes: 9 EGFR mutations, 9 KRAS mutations and 14 FGFR1 copy number gains. Mutations in the PI3K pathway were detected in 44 (7%) of the tumors. Among them, 8 cases enrolled in the investigator-initiated phase II study of gedatolisib (UMIN 000020585). Survival data was available in 463 patients receiving platinum-based chemotherapy. Multivariate analysis revealed that the presence of PIK3CA mutation (HR; 2.56; 95% CI 1.19 – 5.52; p = 0.016) and MYCN amplification (HR; 4.36; 95% CI 1.91 – 9.97; p < 0.001) were significantly associated with unfavorable survival. The frequency of amplifications in MYC family genes was higher in the samples obtained ≥ 90 days after the first-line platinum-based chemotherapy (18.1%) than in those < 90 days (8.1%, p = 0.01), suggesting MYC family amplification as one of the resistance mechanisms. Conclusions: This large-scale nationwide screening system is helpful for identifying therapeutically relevant genetic alterations, prognostic prediction, and exploring resistance mechanism in SCLC. Updated screening results will be presented at the 2019 ASCO Annual Meeting. Clinical trial information: UMIN000018656.

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Thioredoxin Reductase as a Novel and Efficient Plasma Biomarker for the Detection of Non-Small Cell Lung Cancer: a Large-scale, Multicenter study

Scientific Reports ◽

10.1038/s41598-018-38153-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Suofu Ye ◽

Xiaofeng Chen ◽

Yi Yao ◽

Yueqin Li ◽

Ruoxuan Sun ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Multicenter Study ◽

Large Scale ◽

Thioredoxin Reductase ◽

Small Cell ◽

Small Cell Lung ◽

Plasma Biomarker

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Characterizing the Feasibility and Performance of Real-World Tumor Progression End Points and Their Association With Overall Survival in a Large Advanced Non–Small-Cell Lung Cancer Data Set

JCO Clinical Cancer Informatics ◽

10.1200/cci.19.00013 ◽

2019 ◽

pp. 1-13 ◽

Cited By ~ 14

Author(s):

Sandra D. Griffith ◽

Rebecca A. Miksad ◽

Geoff Calkins ◽

Paul You ◽

Nicole G. Lipitz ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Real World ◽

Large Scale ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

Data Set ◽

End Points

PURPOSE Large, generalizable real-world data can enhance traditional clinical trial results. The current study evaluates reliability, clinical relevance, and large-scale feasibility for a previously documented method with which to characterize cancer progression outcomes in advanced non–small-cell lung cancer from electronic health record (EHR) data. METHODS Patients who were diagnosed with advanced non–small-cell lung cancer between January 1, 2011, and February 28, 2018, with two or more EHR-documented visits and one or more systemic therapy line initiated were identified in Flatiron Health’s longitudinal EHR-derived database. After institutional review board approval, we retrospectively characterized real-world progression (rwP) dates, with a random duplicate sample to ascertain interabstractor agreement. We calculated real-world progression-free survival, real-world time to progression, real-world time to next treatment, and overall survival (OS) using the Kaplan-Meier method (index date was the date of first-line therapy initiation), and correlations between OS and other end points were assessed at the patient level (Spearman’s ρ). RESULTS Of 30,276 eligible patients,16,606 (55%) had one or more rwP event. Of these patients, 11,366 (68%) had subsequent death, treatment discontinuation, or new treatment initiation. Correlation of real-world progression-free survival with OS was moderate to high (Spearman’s ρ, 0.76; 95% CI, 0.75 to 0.77; evaluable patients, n = 20,020), and for real-world time to progression correlation with OS was lower (Spearman’s ρ, 0.69; 95% CI, 0.68 to 0.70; evaluable patients, n = 11,902). Interabstractor agreement on rwP occurrence was 0.94 (duplicate sample, n = 1,065) and on rwP date 0.85 (95% CI, 0.81 to 0.89; evaluable patients n = 358 [patients with two independent event captures within 30 days]). Median rwP abstraction time from individual EHRs was 18.0 minutes (interquartile range, 9.7 to 34.4 minutes). CONCLUSION We demonstrated that rwP-based end points correlate with OS, and that rwP curation from a large, contemporary EHR data set can be reliable, clinically relevant, and feasible on a large scale.

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Therapeutic impact of mutation subtypes and concomitant STK11 mutations in KRAS–mutated non-small cell lung cancer (NSCLC): A result of nationwide genomic screening project (LC-SCRUM-Japan).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.9589 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 9589-9589 ◽

Cited By ~ 1

Author(s):

Yutaro Tamiya ◽

Yoshitaka Zenke ◽

Shingo Matsumoto ◽

Naoki Furuya ◽

Tomohiro Sakamoto ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Kras Mutation ◽

Progression Free Survival ◽

Genetic Alterations ◽

Small Cell ◽

Small Cell Lung ◽

Kras Mutations ◽

Genomic Screening

9589 Background: KRAS mutations are one of the common oncogene drivers in non-small cell lung cancer (NSCLC), and the development of several targeted drugs for KRAS-mutated NSCLC is now ongoing. However, the clinical impact of KRAS mutation subtypes or concomitant other gene mutations in NSCLC patients (pts) remains unclear. Methods: In a nationwide genomic screening project (LC-SCRUM-Japan), we have prospectively analyzed lung cancer pts for genetic alterations and tumor mutation burden (TMB) by next-generation sequencing system, and for PD-L1 expression by immunohistochemistry (22C3 antibody). The therapeutic efficacy and survival of KRAS-mutated non-squamous (non-sq) NSCLC pts were evaluated using a clinico-genomic database of the LC-SCRUM-Japan. Results: A total of 5166 non-sq NSCLC pts enrolled from 2015 to 2019. KRAS mutations were detected in 794 pts (15%; G12C/G12D/G12V/G12A/G13X/others = 232/186/165/66/61/84). Among the 794 pts, TMB and PD-L1 expression were analyzed in 128 and 79, respectively, and 218 received PD-1/PD-L1 inhibitors (IO) after 1st-line chemotherapy. The median age was 66 years (range, 29-89). 142 pts (65%) were male and 172 (78%) were smokers. Concomitant STK11 mutations were detected in 33 pts (15%) with no difference in the mutation frequency among KRAS mutation subtypes. KRAS G12C was significantly associated with high TMB (≥ 10 mut/Mb) (p = 0.03), and KRAS G12C or G12V with high PD-L1 expression (≥ 50%) (p = 0.02). In pts who received IO, median progression-free survival (mPFS) was significantly longer in pts with KRAS G12C or G12V than in those with other KRAS mutations (4.7 vs 2.0 months, hazard ratio (HR) 0.58 [95%CI 0.43-0.78], p < 0.01). Among pts with KRAS G12C or G12V, mPFS of IO was significantly shorter in pts with concomitant STK11 mutations than in those without (1.8 vs. 5.7 months, HR 1.97 [95%CI 1.06-3.41], p = 0.02). These correlations were not observed in platinum-containing chemotherapy (Plt-CTx). There were also no significant differences in IO and Plt-CTx efficacies between with and without other concomitant mutations, such as TP53, RB1, CDKN2A and PTEN mutations. Conclusions: Non-sq NSCLC pts with KRAS G12C/V were more sensitive to IO therapies than those with other KRAS mutations, but KRAS G12C/V-positive pts with concomitant STK11 mutations were less sensitive than those without. These results could be highly informative in the development of novel targeted therapies for KRAS-mutated NSCLC.

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Establishment of the first international large-scale, genomic screening platform to identify patients with rare oncogene drivers in non-small cell lung cancer (NSCLC) in East Asia.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.9605 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 9605-9605

Author(s):

Shingo Matsumoto ◽

Caicun Zhou ◽

Chih-Hsi Kuo ◽

Kiyotaka Yoh ◽

Terufumi Kato ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trials ◽

Small Cell Lung Cancer ◽

Targeted Therapies ◽

Large Scale ◽

East Asian ◽

Small Cell ◽

Small Cell Lung ◽

Genomic Screening ◽

Screening Platform

9605 Background: A rapidly increasing number of oncogenic drivers have been identified in non-small cell lung cancer (NSCLC), and most of them occur in less than 5% of patients. Large-scale genomic screening to identify patients with rare driver alterations is thus necessary to enable precision medicine and to support the development of novel targeted therapies and companion diagnostics (CDx). Methods: A lung cancer genomic screening project (LC-SCRUM-Asia) capturing clinical outcome was established in 2013 with 206 institutions in Japan and 5 in Taiwan currently participating. A separate genomic screening project with similar structure was established in China (LC-IRICA-China) in collaboration with LC-SCRUM-Asia in 2019 (3 institutions enrolling, 17 about to open, 63 undergoing review). Samples are analyzed by a multi-gene PCR panel and targeted next-generation sequencing. The target is to enroll 70000 NSCLC patients (20000 from LC-SCRUM-Asia and 50000 from LC-IRICA-China) by 2022. Results: From March 2013, a total of 9383 lung cancer patients were enrolled in LC-SCRUM-Asia, and from October 2019, 1649 pts were included in LC-IRICA-China (January 2020). The rates of genomic alterations in LC-SCRUM-Asia: EGFR (17%) of which ex20ins (2%), KRAS (13%) of which G12C (4%), ALK fusions (2%), ROS1 fusions (2%), RET fusions (2%), HER 2 ex20ins (3%), MET ex14skip (2%), BRAF V600E (1%), NRG1 fusions (0.2%) and NTRK3 fusions (0.03%). Corresponding rates in the initial 243 pts in LC-IRICA China: EGFR (45%) of which ex20ins (2%), KRAS (8%), ALK (5%), ROS1 (2%), RET (1%), HER2 (2%), MET ex14skip (1%), BRAFV600E (1%). Through the screening, 266 patients from Japan and Taiwan were enrolled into genotype-matched clinical trials of unapproved targeted drugs. In Japan, ROS1-, BRAF- and TRK-targeted therapies were successfully approved based on these clinical trials, and a NGS-based multi-gene CDx for EGFR/ALK/ROS1/BRAF targeted-therapies was approved based a concordance study using archival samples from the project. Conclusions: An East Asian international genomic screening platform has been established to enable precision medicine for patients, accelerate drug and diagnostic development in patients with very rare alterations and to help provide a deeper understanding of the underlying biology of NSCLC in East Asian patients. The screening network will be further expanded to other countries in East Asia in the near future.

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A nationwide genomic screening project for small cell lung cancer in Japan (LC-SCRUM-Japan)

Annals of Oncology ◽

10.1093/annonc/mdx697.043 ◽

2017 ◽

Vol 28 ◽

pp. ix84

Author(s):

Haruko Daga ◽

Shigeki Umemura ◽

Yuichiro Ohe ◽

Tetsuhiro Shiota ◽

Masaki Fujita ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Genomic Screening

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Efficacy of definite concurrent chemoradiotherapy for patients with limited-disease small-cell lung cancer: a retrospective, nationwide, population-based cohort study

10.21203/rs.3.rs-42549/v2 ◽

2020 ◽

Author(s):

Seoree Kim ◽

Ji Hyung Hong ◽

Soo-Yoon Sung ◽

Yeo Hyung Kim ◽

Sang Hoon Chun ◽

...

Keyword(s):

Lung Cancer ◽

Cohort Study ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Large Scale ◽

Concurrent Chemoradiotherapy ◽

Single Agent ◽

Small Cell ◽

Small Cell Lung ◽

Limited Disease

Abstract Background: Small-cell lung cancer (SCLC) is a highly proliferative, rapidly growing tumor with a poor prognosis, even in cases of limited disease (LD). Timely and accurate high-intensity therapy is necessary. For concurrent chemoradiotherapy (CCRT), etoposide/platinum (EP)-based regimens are recommended, although irinotecan/platinum (IP)-based regimens are also effective with radiotherapy. This large-scale, retrospective, nationwide cohort study aimed to analyze the efficacy of CCRT in patients with LD-SCLC. Methods: Population data registered between January 2008 and December 2018 was extracted from the Health Insurance Review and Assessment Service of Korea database. Survival outcomes of 4,446 LD-SCLC patients who received CCRT were analyzed. Results: Patients who received EP-CCRT (n = 4,187) showed better progression-free survival (PFS: 11.2 months) and overall survival (OS: 22.2 months) than those who received IP-CCRT (n = 259; PFS: 9.6 months, P = 0.0477; OS: 16.4 months, P <0.0001). When CCRT failed, dual-agent chemotherapy (n = 925; OS: 9.1 months) provided a better survival benefit than single-agent chemotherapy (n = 815; OS: 7.5 months). IP-based chemotherapy resulted in better OS (9.6 months) than EP-based chemotherapy (7.1 months, P = 0.017) in platinum-resistant relapsed patients; the opposite was observed for platinum-sensitive relapsed patients (OS: EP, 17.2 months; IP, 6.6 months; P <0.0001). Poisson regression analysis demonstrated that age, EP-CCRT, and hypercholesterolemia retained significant associations with OS after adjustment for all variables. Conclusion: In the Korean population, the effects of EP-CCRT on OS and PFS are significantly more favorable than those of IP-CCRT.

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