A nationwide genomic screening project 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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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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Nationwide genomic screening network for the development of novel targeted therapies in advanced non-small cell lung cancer (LC-SCRUM-Japan).

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.8093 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. 8093-8093 ◽

Cited By ~ 2

Author(s):

Shingo Matsumoto ◽

Kiyotaka Yoh ◽

Takashi Seto ◽

Takuma Yokoyama ◽

Haruyasu Murakami ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Targeted Therapies ◽

Small Cell ◽

Small Cell Lung ◽

Genomic Screening

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

Annals of Oncology ◽

10.1093/annonc/mdy374.013 ◽

2018 ◽

Vol 29 ◽

pp. vii54

Author(s):

Norio Okamoto ◽

Shigeki Umemura ◽

Taku Nakagawa ◽

Shingo Miyamoto ◽

Kenichiro Kudo ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Large Scale ◽

Small Cell ◽

Screening System ◽

Small Cell Lung ◽

Genomic Screening

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

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.8518 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 8518-8518 ◽

Cited By ~ 1

Author(s):

Haruyasu Murakami ◽

Shigeki Umemura ◽

Masahiro Shinoda ◽

Masato Shingyoji ◽

Yukari Ogawa ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Targeted Therapies ◽

Small Cell ◽

Small Cell Lung ◽

Genomic Alterations ◽

Activating Mutations ◽

Genomic Screening ◽

Inactivating Mutations

8518 Background: Recent genomic studies of small-cell lung cancer (SCLC) have identified promising therapeutic strategies for this highly lethal form of cancer. Thus, we established a nationwide lung cancer genomic screening project in Japan (LC-SCRUM-Japan) to identify SCLC patients harboring targetable genomic alterations for the development of novel targeted therapies. Methods: The samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 cancer-related genes. Results: As of December 2016, 133 institutions were participating and 295 patients had been enrolled. The median age was 69 years (range, 14-90 years). Two hundred seventeen (74%) were male and most patients (93%) were smokers. Among 268 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 198 (74%) /82 (31) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 10 (4%) /13 (5) /4 (1) of cases, respectively. The NGS analysis also showed that 62 (23%) of cases had at least one targetable genomic alterations, including 7 EGFR activating mutations (3%), 6 KRAS activating mutations (2%), and 8 FGFR1 copy number gains (3%). No case was positive for ALK or ROS1 fusions. Never-smokers (71% vs. 5%, p<0.001) were significantly frequent in the EGFR type compared to the others. The KRAS type showed significantly poor progression free survival (PFS) of the first-line chemotherapy compared to the others (median PFS 1.2 vs. 6.1 months, respectively; p<0.001). Mutations in the PI3K/AKT/mTOR pathway were detected in 22 (8%) of the tumors: 10 PIK3CA mutations (4%), 9 PTEN inactivating mutations (3%) and 3 TSC2 inactivating mutations (1%). Among them, a case with PTEN mutation was enrolled in the investigator initiated phase II study of gedatolisib named “EAGLE-PAT” (UMIN 000020585). Conclusions: We identified a series of targetable genomic alterations in SCLC. This nationwide screening system is helpful for identifying targetable genomic alterations and their clinical features, contributing to the development of novel targeted therapies for this disease. Updated screening results will be presented at the 2017 ASCO Annual Meeting.

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