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Background Many previous studies have demonstrated that minor-frequency pretreatment T790M mutation (preT790M) could be detected by ultrasensitive methods in a considerable number of treatment-naïve, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC) cases. However, the impact of preT790M in resected cases on prognosis remains unclear. Methods We previously reported that preT790M could be detected in 298 (79.9%) of 373 surgically resected, EGFR-mutated NSCLC patients. Therefore, we investigated the impact of preT790M on recurrence-free survival (RFS) and overall survival (OS) in this cohort by multivariate analysis. All patients were enrolled from July 2012 to December 2013, with follow-up until November 30, 2017. Results The median follow-up time was 48.6 months. Using a cutoff value of the median preT790M allele frequency, the high-preT790M group (n = 151) had significantly shorter RFS (hazard ratio [HR] = 1.51, 95% confidence interval [CI]: 1.01–2.25, P = 0.045) and a tendency for a shorter OS (HR = 1.87, 95% CI: 0.99–3.55, P = 0.055) than the low-preT790M group (n = 222). On multivariate analysis, higher preT790M was independently associated with shorter RFS (high vs low, HR = 1.56, 95% CI: 1.03–2.36, P = 0.035), irrespective of advanced stage, older age, and male sex, and was also associated with shorter OS (high vs low, HR = 2.16, 95% CI: 1.11–4.20, P = 0.024) irrespective of advanced stage, older age, EGFR mutation subtype, and history of adjuvant chemotherapy. Conclusions Minor-frequency, especially high-abundance of, preT790M was an independent factor associated with a poor prognosis in patients with surgically resected, EGFR-mutated NSCLC.

Background To report the follow up data and clinical outcomes of the JME study (UMIN 000008177), a prospective, multicenter, molecular epidemiology examination of 876 surgically resected non‐small‐cell lung cancer (NSCLC) cases, and the impact of somatic mutations (72 cancer‐associated genes) on recurrence‐free survival (RFS) and overall survival (OS). Methods Patients were enrolled between July 2012 and December 2013, with follow up to 30th November 2017. A Cox proportional hazards model was used to assess the impact of gene mutations on RFS and OS, considering sex, smoking history, age, stage, histology, EGFR, KRAS, TP53, and number of coexisting mutations. Results Of 876 patients, 172 had ≥2 somatic mutations. Median follow‐up was 48.4 months. On multivariate analysis, number of coexisting mutations (≥2 vs 0 or 1, HR = 2.012, 95% CI: 1.488‐2.695), age (≥70 vs, A prospective, multi‐center, molecular epidemiology study of 876 surgically resected non‐small cell lung cancer cases, and the impact of somatic mutations (72 cancer‐associated genes) on recurrence‐free survival and overall survival (OS). A smaller number of co‐existing mutations, earlier stage, and younger age were associated with longer recurrence free survival and OS, while epidermal growth factor receptor mutations were significantly associated with improved OS.

A phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non-small cell lung cancer was conducted.We used chemotherapy of a cisplatin doublet and 2 dose levels of radiation with accelerated hyperfractionation. The radiation dose levels were: a total dose of 60 Gy in 40 fractions at level 1, and 66 Gy in 44 fractions at level 2. Eligible patients with unresectable stage III non-small cell lung cancer received cisplatin and vinorelbine. Radiation therapy started on day 2 of chemotherapy and was delivered twice daily for 5 days a week.Total 12 patients were enrolled, with 6 patients each at dose levels 1 and 2. Dose-limiting toxicity was noted in 2 patients at level 1; one patient had grade 3 febrile neutropenia and the other patient had grade 3 esophagitis. No dose-limiting toxicity was noted in the 6 patients at level 2. Grade 3 to 4 leukopenia, neutropenia, and anemia were noted in 11 (92%), 9 (75%), and 8 (67%) of the total 12 patients, respectively. Grade 3 anorexia and infection were noted in 2 patients (17%) at each level. Grade 3 nausea, fatigue, esophagitis, and febrile neutropenia were noted in 1 patient (8%) at each level. The response rate in the total 12 patients was 83.3%. The median progression-free survival time and the median overall survival time were 10.7 and 24.2 months, respectively.Sixty-six gray in 44 fractions is the recommended dose for the following phase II study.

Objectives Non-small cell lung cancer (NSCLC) and chronic obstructive pulmonary disease (COPD) have been proposed to have a mutual developmental mechanism, but their association has not been fully understood. We aimed to examine the association of the mutational landscape of NSCLC with co-morbid COPD. Materials and methods A total of 197 surgical specimens of early stage NSCLC were retrospectively collected from two independent sources, namely, the Japan Molecular Epidemiology for Lung Cancer Study and the Osaka City University Hospital cohort from 2010 to 2013. COPD and its severity were defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines and grading system. For molecular profiling of NSCLC patients with COPD, the extracted DNAs were deep-sequenced using next generation sequence technologies for somatic mutations in a maximum 72 cancer-associated genes. Logistic regression analysis was performed to evaluate the impact of COPD on the somatic mutations. Results The COPD group (n = 77), including 56 GOLD 1 and 21 GOLD 2 or 3 patients, had 58 squamous cell lung carcinoma (SCC) cases and 19 adenocarcinoma cases. The non-COPD group (n = 120) had 53 SCC cases, 64 adenocarcinoma cases, and three cases with other histology. The frequency of PIK3CA mutation was significantly higher in the COPD group than in the non-COPD group (10.4% vs. 1.7%, p = 0.015). Meanwhile, NFE2L2 mutation was observed only in SCC cases, with no difference in the frequency between the two groups (17.2% vs. 17.0%). In the multivariate logistic regression model with consideration for COPD status, age, smoking dose, pathological stage, and histology, significantly more PIK3CA mutation was observed in the presence of COPD (odds ratio = 5.31, 95% CI: 1.03–27.29, p = 0.046). Conclusions PIK3CA mutation is a distinctive genetic feature of NSCLC with COPD, regardless of age, smoking dose, pathological stage, and histology.

Objectives Low-frequency epidermal growth factor receptor (EGFR) T790M mutation could be detected by ultrasensitive methods in EGFR tyrosine kinase inhibitor (TKI)-naive non-small cell lung cancer (NSCLC). However, the impact of pretreatment T790M (preT790M) on the efficacy of EGFR-TKIs and on resistance remains unclear. Materials and methods Two independent cohorts consisting of advanced EGFR-mutated NSCLC patients treated with first-line EGFR-TKIs, a derivation cohort that started treatment between August 2013 and July 2016 (cohort A, n = 44) and a validation cohort between August 2016 and December 2017 (cohort B, n = 22), were examined in this study. Among these, 28 patients underwent re-biopsy at disease progression. DNAs from pretreatment tumor biopsy samples and re-biopsy samples were assessed to detect T790M by the Cobas EGFR Mutation Test v2 (Cobas) and for quantitating T790M by droplet digital polymerase chain reaction (ddPCR). Results Detection rates of preT790M were 40.9% (18/44) in cohort A and 45.5% (10/22) in cohort B by ddPCR, and none by Cobas. A cutoff value of 0.3% for dividing into high- vs. low-preT790M allele frequency was determined by receiver operating characteristic curve analysis in cohort A. Progression-free survival (PFS) was significantly shorter in the high- preT790M group (n = 12) than in the low-preT790M (n = 6) and negative (n = 26) groups (combined low-preT790M) (median: 6.9 vs. 13.8 months, P = 0.00073). These observations were validated in cohort B [median: 6.2 (n = 5) vs. 15.3 months (n = 17), P = 0.0029]. In 28 paired biopsies, Cobas detected post-progression T790M in 60% (3/5) of the high-preT790M, in 57% (4/7) of the low-preT790M, and in 56% (9/16) of the negative-preT790M groups. Conclusion EGFR-mutated NSCLC with high preT790M had significantly shorter PFS on EGFR-TKIs. However, preT790M abundance may not necessarily confer post-TKI T790M resistance.

e21035 Background: The role of estrogen receptor status in the carcinogenesis of lung cancer remains elusive. A census of clonal and sub-clonal mutations has been defined through the analyses of evolutionary histories of cancers. We previously reported a prospective multicenter molecular epidemiology study (JME study; Kawaguchi T, J Clin Oncol 2016), which included the expression levels of estrogen receptors β (ER) using immunohistochemistry(IHC) and the mutational profile using next generation sequencing as well as solid smoking information and reproductive/ hormonal risk factors from the detailed questionnaire. Methods: Utilizing the data of the JME study, the impact of ER in lung cancer development was explored. All the patients underwent surgery. In 441 ever- and 435 never-smokers, ER were observed in 46.4% and 53.5%, respectively. The cancer-associated 72 gene mutations and 5 gene amplifications examined in this study included EGFR, SMAD4, APC, FBXW7, BRAF, STK11, PIK3CA, TP53, PTEN, KRAS, CTNNB1, NFE2L2, NF1, and MET. ALK fusion was detected by IHC. Patients were enrolled between July 2012 and December 2013, with follow up until November 30th, 2017.Cox proportional hazards models were used to assess the ER expression on relapse free survival (RFS) and overall survival (OS). A logistic regression model was applied to assess the impact of ER (positive vs. negative) on gene alterations, using sex, smoking history, age and stage as independent variables. Results: ER expression was significantly higher in never smokers (vs. ever smokers; p = 0.022) and earlier stage (stage I vs. II-IV; p = 0.002). Patients with ER positive tumors had a longer RFS than those with negative tumors (RFS rate at 4 years: 33.7 vs. 26.5%; p = 0.021), however, there was no significant difference in OS between the two groups (p = 0.108). In the impact of ER status on the gene alterations, mutations in EGFR (p = 0.003), TP53 (p = 0.007) and CTNNB1 (p = 0.027) were significantly associated with ER expression. Multivariate analysis showed that EGFR mutations (OR = 1.394, 95%CI: 1.029-1.890, p = 0.032) and CTNNB1 mutations (OR = 0.272, 95%CI: 0.087-0.853, p = 0.026) were significantly associated with ER expression, while there was a trend for significance with TP53 mutations (OR = 0.737, 95%CI: 0.537-1.011, p = 0.059). Conclusions: ER positive status triggered the clonal EGFR mutations and suppressed the sub-clonal mutations of TP53 and CTNNB1. It is suggested that ER plays a critical role in the alterations of EGFR/TP53/ CTNNB1 axis in lung cancer evolution.

e20017 Background: P has widely been used for the risk assessment of lung cancer and chronic obstructive pulmonary disease (COPD). We previously reported that mutations in KRAS, TP53, and EGFR were also associated with P from a prospective multicenter molecular epidemiology study (JME study; Kawaguchi T, J Clin Oncol 2016). Recently, D alone has been reported to provide stronger risk estimates of COPD than P. Here, we show the comparison of these two indices in predicting the risk of smoking-related oncogenic mutations in NSCLC, utilizing the database from the JME study including detailed smoking information and the mutational profile by next generation sequencing. Methods: In 439 ever- and 437 never-smokers, the frequency of mutations in KRAS, TP53 and EGFR were 9.4, 26.8 and 42.5%, respectively, and smoking-related cytosine to adenine base substitution (C > A) was observed in 12.7 % of cases. AUC values (area under the ROC curves) for logistic regression determined from P and D to predict the mutations or C > A change were compared, considering gender, age, stage and histology as covariates. Results: The median of P and D were 43 (1-189) and 41 (years, 1-65) in smokers, respectively. The AUC values in EGFR and KRAS were numerically higher than others, suggesting stronger association with smoking. There was no significant difference in AUC values between P and D in TP53, EGFR and C > A, and P was a significantly better estimate of KRAS mutations (table). Conclusions: P remains the standard method to evaluate the risk of oncogenic mutations in NSCLC. D, however, warrants further investigation as a simpler alternative to P.[Table: see text]

Purpose Oncogenic driver mutations are critical for lung cancer development and serve as therapeutic targets. However, their associations with environmental factors are not fully understood. We aimed to elucidate the relationship between tumor developmental biology and exposure to environmental factors. Patients and Methods This was a prospective, multicenter, molecular epidemiology study. Eligible patients were those with newly diagnosed stages I to IIIB non–small-cell lung cancer (NSCLC) who underwent surgery. The tumors were examined for somatic mutations in 72 cancer-associated genes by targeted deep sequencing, estrogen receptor β (ERβ) expression using immunohistochemical staining, and infection with any of 37 types of human papillomavirus (HPV) using a polymerase chain reaction–based microarray system. Detailed information on patient demographics and environmental factors was obtained from a comprehensive questionnaire. Results From July 2012 to December 2013, 957 patients were enrolled, and molecular analyses were performed on 876 samples (from 441 ever- and 435 never-smokers). Oncogenic driver mutations in P53 and KRAS increased proportionally with smoking status, whereas mutations in EGFR and SMAD4 decreased. KRAS mutations in smokers and SMAD4 mutations were observed more frequently in proportion to body mass index. TP53 and NFE2L2 mutations were observed more frequently in advanced NSCLC stages. As for never-smokers, no environmental factors were significantly associated with mutational changes. EGFR mutations and TP53 mutations were observed more frequently in women and in men, respectively. Mutations in these two genes were also potentially associated with ERβ expression. Only three patients (0.3%) were HPV positive. Conclusion The mutational spectrum is associated with smoking, body mass index, and other environmental factors, as well as with ERβ expression. Little association was observed between HPV and NSCLC.

Background: T790M mutation in EGFR accounts for nearly 50% of the acquired mechanism of resistance to EGFR-tyrosine kinase inhibitors (TKIs). Previous studies suggested that EGFR T790M mutation was also detected in a considerable number of EGFR-TKI-naïve non-small-cell lung cancer (NSCLC) patients utilizing ultrasensitive detection methods such as droplet digital PCR (ddPCR). Here we investigated the significance of low-frequency pretreatment EGFR T790M mutation (preT790M) and its association with cancer molecular heterogeneity in the efficacy of EGFR-TKIs. Materials and methods: Fifty-two advanced NSCLC patients harboring activating EGFR mutations treated with first-line EGFR-TKIs at Osaka City University Hospital between August 2013 and July 2016 were enrolled in the study. DNAs from tumor biopsies at diagnosis were available from 44 patients for detecting preT790M by the cobas® EGFR Mutation Test v2 (cobas) and ddPCR (RainDance Technologies) and those from 33 were available for assessing the actionable mutations in 50 genes by next-generation sequencing (NGS). NGS was performed on the Ion PGM using Ion AmpliSeq Cancer Hotspot Panel v2 (Life Technologies). Paired biopsies before EGFR-TKIs treatment and at disease progression (PD) were obtained from 15 patients to assess the T790M mutation by cobas. Results: The overall detection rate of preT790M by ddPCR was 40.9% (18/44), while not detected in any case by cobas. The median progression free survival (mPFS) was 10.0 months for the patients with preT790M and 13.5 months for those without preT790M (p=0.288), respectively. When divided into 3 categories based on the frequency of preT790M such as high with T790M allele frequency (AF) >0.3%, low with AF ≤0.3% and undetected, 12 patients with high AF had a relatively shorter mPFS than 6 with low AF (p=0.090) and 26 without detectable preT790M (p=0.046) (7.7 vs 17.1 vs 13.5 months, respectively). NGS revealed 18 additional coexisting actionable mutations in 15 out of 33 patients: TP53 (n=7), PIK3CA (n=5), CTNNB1 (n=3) and uncommon EGFR (n=3). There was a trend for patients with higher preT790M AF to harbor less additional coexisting mutations (27% with high AF, 60% with low AF and 53% without preT790M, p=0.320). In 15 paired biopsies, T790M mutation was detected in 60% (9/15) at PD by cobas in the clinical setting; 67% (2/3) with high AF, 50% (1/2) with low AF and 60% (6/10) without detectable preT790M, suggesting T790M mutation after first-line EGFR-TKIs developed from both clonal selection and secondary acquisition models. Conclusion: Results of our study indicated that EGFR-mutated NSCLCs with higher AF preT790M >0.3% had significantly shorter duration of response to EGFR-TKIs. In addition, the AF of preT790M in EGFR-mutated NSCLC may be associated with coexisting actionable mutation load potentially affecting the efficacy of EGFR-TKIs. Citation Format: Yoshiya Matsumoto, Kenji Sawa, Jun Oyanagi, Mitsuru Fukui, Naoki Yoshimoto, Tomohiro Suzumura, Shigeki Mitsuoka, Kazuhisa Asai, Tatsuo Kimura, Nobuyuki Yamamoto, Tomoya Kawaguchi, Kazuto Hirata, Yasuhiro Koh. Predictive impact of low-frequency pretreatment T790M mutation in patients with EGFR-mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors [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 2613.

e20520Background: Several studies including LUX LUNG 3 and 6 have shown that there are biological differences between EGFR exon 19 deletions (del19) and exon 21 L858R mutation (L858R) in lung adeno...

8549Background: We previously reported molecular profiling as a primary endpoint in a prospective multicenter molecular epidemiology study, collecting 876 surgically resected NSCLC and examining 72...

Purpose Patients with advanced non-small cell lung cancer (NSCLC) harboring a sensitive epidermal growth factor receptor (EGFR) mutation have been shown to exhibit a marked response to EGFR-tyrosine kinase inhibitor (TKI) treatment. Pemetrexed and gefitinib were reported to have a schedule-dependent cytotoxic synergism. We evaluated the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in EGFR-mutated NSCLC patients. Patients and methods Systemic therapy-naive patients with advanced non-squamous NSCLC harboring a sensitive EGFR mutation were included in this study. Pemetrexed was administered on day 1 at a dose of 500mg/m 2 , and gefitinib was sequentially administered on days 2–16. This treatment regimen was repeated every 3 weeks until disease progression. Results Twenty-six patients were enrolled in this study. The median number of treatment cycles was 16 (range, 1–35). The overall response rate (ORR) was 84.6% (95% confidence interval [CI], 70.7–98.5%), and the disease control rate (DCR) was 96.2% (95% CI, 88.9–100%). Grade 3/4 hematological toxicities included neutropenia (15.4%), leukopenia (7.7%), and anemia (3.8%). No grade 4 non-hematological toxicities were observed. The main grade 3 non-hematological toxicities were infection (11.5%), increased alanine aminotransferase (11.5%) and aspartate aminotransferase (7.7%) levels, fatigue (3.8%), diarrhea (3.8%), and pneumonitis (3.8%). We observed a median progression-free survival (PFS) of 18.0 months (95% CI, 15.0–21.0 months) and a median survival time (MST) of 32.0 months (95% CI, 28.5–35.5 months). There were no treatment-related deaths. Conclusions The combination regimen used in this study showed a high ORR, long median PFS, and acceptable toxicity. A future randomized trial on pemetrexed plus gefitinib compared with gefitinib alone is warranted.

8526Background: A common developmental mechanism has been proposed between NSCLC and COPD; however the association is not fully understood. We conducted a prospective, multicenter molecular epidemi...

e18517 Background: Non-small cell lung cancer (NSCLC) in never smokers constitutes higher proportions of females and East Asian, which implies that sex hormones contribute to the carcinogenesis the...