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Tomoya Kawaguchi
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MS 02 - Ethnic Differences: Biology or Myth (ID 524)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Regional Aspects/Health Policy/Public Health
- Presentations: 1
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MS 02.02 - Molecular Epidemiology (ID 7728)
11:15 - 11:30 | Presenting Author(s): Tomoya Kawaguchi
- Abstract
- Presentation
Abstract:
It has been recognized that ethnic differences contribute to disparities in carcinogenesis and treatment outcomes in lung cancer. The disparities can be due to the variety of mutations which are developed and triggered by the evolutionary forces over time and across populations. Although several single nucleotide polymorphisms as genome-wide significant signals can be associated with the mutations, environmental factors including smoking, dust exposures, obesity and potential viral infections (human papilloma virus) are also essential to the genomic diversity. Frequent occurrence of EGFR mutations is likely to be a feature of lung adenocarcinoma in Asian female never smokers including Japanese, while KRAS mutations are more common in Caucasian smokers. Because Japanese women are likely to have more environmental tobacco smoke (ETS) exposure, we conducted a single-center prospective study to examine an association between ETS and EGFR mutations in never smokers with non-small cell lung cancer (NSCLC) and clarify the reason for the unique background. We showed the development of EGFR mutations was inversely proportional to the dose of ETS exposure in never-smokers.[1] However, there are conflicting data published regarding the relationship, and mystery of the mutation still deepens. Based on recent developments in next-generation sequencing techniques detecting many genetic alterations, the Japan Molecular Epidemiology for lung cancer (JME) study has been designed and conducted beyond the scope of EGFR and KRAS mutations.[2] The aim of this prospective, multicenter, molecular epidemiology study is to elucidate the relationship between tumor developmental biology and exposure to environmental factors. A total of 876 surgical samples from 441 ever- and 435 never-smokers with early stage NSCLC underwent molecular analyses. In smokers, the most frequent mutations were TP53 (38%), EGFR (20%), KRAS (13%), NFE2L2 (6%) and PIK3CA (4%), whereas in never-smokers, EGFR (61%), TP53 (15%), KRAS (4%) and PIK3CA (2%) were the most frequent. Dominant base substitutions were C>A transversion and C>T transition in TP53, C>A transversion in KRAS, C>G transversion in NFE2L2 and C>T transition in PIK3CA. Mutations in P53 and KRAS increased proportionally with smoking status, while EGFR mutations decreased. KRAS mutations in smokers were more frequently observed in proportion to body mass index. As for the ethnic difference on these mutations, our data can be compared with another integrative genomic analysis from The Cancer Genome Atlas (TCGA).[3,4 ]The study population in the TCGA was mostly Caucasian smokers with mixed smoking dose in early stage NSCLC, while the JME study was exclusively in Japanese patients, half of which were smokers and the other half never-smokers in the similar stage. In adenocarcinoma, the frequency of EGFR mutations was inversely proportional to the degree of smoking exposure both in the US and Japan. The mutation rates were always higher in Japan than in the US in each smoking status. While in KRAS and TP53 mutations, the frequencies increased proportionally as smoking; however, the mutation rates were always higher in the US than in Japan. The mutation rates of KEAP1, NF1 and STK11 seemed to be higher in the US than in Japan, regardless of smoking status (Table). In squamous cell carcinoma, KEAP1 and NF1 were also lower in Japan as well as TP53. The difference in ethnicity and potentially unveiled environmental factors can explain differences in the mutations prevalence. Figure 1 From the beginning, the JME study has been designed to investigate the relationship between ethnicity and NSCLC carcinogenesis. Our potential counterpart study is S0424 which is a molecular epidemiological study in the US by using a detailed questionnaire and NSCLC tissue specimens from smoker and never-smoker men and women with early stage NSCLC. The JME study follows and extends the concept of S0424 by using a similar questionnaire that will allow us for direct comparison of data. We believe that the real value of genomic data will be realized only when they are linked to high-quality and solid clinical information, allowing us to identify precise genotype–phenotype associations. In conclusion, ethnicity is an important and complex characteristic that needs to be recognized and considered even in the era of precision medicine. We should collaborate to share the data from different ethnicity and translate them into the clinical practice and the design of a global clinical study. Carefully designed molecular epidemiological studies focused on ethnic differences are warranted. Reference 1. Kawaguchi T, Ando M, Kubo A, et al. Long exposure of environmental tobacco smoke associated with activating EGFR mutations in never-smokers with non-small cell lung cancer. Clinical cancer research 2011;17:39-45. 2. Kawaguchi T, Koh Y, Ando M, et al. Prospective Analysis of Oncogenic Driver Mutations and Environmental Factors: Japan Molecular Epidemiology for Lung Cancer Study. Journal of clinical oncology 2016;34:2247-57. 3. Cancer Genome Atlas Research N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511:543-50. 4. Cancer Genome Atlas Research N. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489:519-25.
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P1.06 - Epidemiology/Primary Prevention/Tobacco Control and Cessation (ID 692)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.06-014 - Higher Body Mass Index Prolongs Survival Time in Non-Small Cell Lung Cancer with Good Performance Status (ID 9657)
09:30 - 09:30 | Author(s): Tomoya Kawaguchi
- Abstract
Background:
Obesity is the accumulation of body fat that has a harmful effect on health and has been increased the risk and mortality of multiple diseases, such as cardiovascular diseases and diabetes. Obesity has been associated with increased risk and mortality of most cancers. On the other hand, obesity is associated with decreased risk of a part of lung cancer. The mechanism to decrease risk of lung cancer in obese individuals is not clear.
Method:
In our hospital, we retrospectively assessed 675 lung cancer patients who were hospitalized for the first time from April 2012 to July 2015. We collected patient data of baseline characteristics, histology, performance status (PS), body mass index (BMI), stage, smoking history, molecular profiling for EGFR, ALK. Patients were stratified into 3 BMI groups based on the WHO classification: underweight (< 18.5 kg/m[2]), normal weight (18.5 to < 25 kg/m[2]), and overweight (≥ 25 kg/m[2]). The classification of obese (≥ 30 kg/m[2]) was included in the overweight group in this study. Overall survival was calculated using the Kaplan-Meier method. We compared overall survival between BMI groups using log rank test.
Result:
In this retrospective cohort study, we assessed 566 patients with non-small cell lung cancer (NSCLC) and 109 patients with small cell lung cancer (SCLC). There were no significant differences in patient characteristics except for smoking history. In SCLC patients, there was no significant difference in overall survival by each BMI group (good PS [0 – 1] group, p = 0.186; poor PS [2 – 4] group, p = 0.809). In NSCLC patients with good PS, overall survival was prolonged in the order of the standard group and the overweight group, in comparison with the underweight group (p = 0.031). In NSCLC patients with poor PS, there was no significant difference in overall survival by each BMI group (p = 0.401). In NSCLC patients with good PS, higher BMI and activating EGFR mutation were associated with longer overall survival in a multivariate analysis (BMI: hazard ratio 0.468, 95% CI 0.253 – 0.855, p = 0.0136; EGFR mutation: hazard ratio 0.476, 95% CI 0.279 – 0.796, p = 0.0044). In SCLC patients with good PS, there was a tendency of longer overall survival in the overweight group than in the underweight group.
Conclusion:
Overweight in NSCLC patients with good PS had significantly improved overall survival.
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-008 - Phase I/II Study of Intermitted Erlotinib in Combination with Docetaxel in Patients with Recurrent NSCLC with Wild-Type EGFR: WJOG 4708L (ID 7556)
09:30 - 09:30 | Author(s): Tomoya Kawaguchi
- Abstract
Background:
Erlotinib (ERL) is modestly active to non-small cell lung cancer (NSCLC) with wild type epidermal growth factor receptor (EGFR). We hypothesized that an intermittent delivery of erlotinib and docetaxel (DOC) would increase efficacy.
Method:
This was a multi-center, single-arm phase I/II study in patients with wild type EGFR NSCLC who failed one prior chemotherapy. The phase I was designed a standard 3+3 dose escalation design to determine feasibility, the maximum tolerated dose (MTD) and phase II recommend dose (RD) of ERL on days 2 to 16, in combination with a fixed dose of 60mg/m[2] DOC on day 1. The phase II primary endpoint was objective response rate (ORR) by independent review committee. This study required 41 patients with expected ORR of 30% and threshold ORR of 10% (one-sided α= 0.025; β=0.1). The target number was 45 patients assuming the loss of follow-up cases. All eligible patients had ECOG performance status of 0/1 and adequate organ functions.
Result:
Between Mar 2009 and Dec 2010, 12 patients were enrolled in the phase I, and between May 2011 and Feb 2015, 46 patients in the phase II. Five patients were excluded from per protocol set, because of deviation of entry criteria. Planned dose escalation was completed without reaching a MTD. The RD was determined as 150 mg/dose of ERL. In the phase II, the ORR was 17.1% (95%CI, 7.2-32.1). The median progression free survival and median overall survival were 3.48 months (95%CI, 3.06-4.50) and 11.27 months (95%CI, 8.61-16.56), respectively. Gender, smoking status, or concomitant drugs which influence the ERL metabolism had no significant differences in ORR, or disease control rate. All 46 patients were evaluable for toxicity. The grade 3 non-hematological toxicities included 9 (19.6%) febrile neutropenia, 7 (15.2%) appetite loss, 3 (6.5%) oral mucositis and 3 (6.5%) infections. The grade 4 hematological toxicities were 31 (67.4%) neutropenia. Two treatment related deaths were observed; interstitial lung disease, and pleural infection.
Conclusion:
Intermittent dosing of ERL plus DOC is clinically feasible, but has no statistically significant improvement of ORR, in patients with recurrent NSCLC with wild type EGFR.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-088a - Phase II Study of Nab-Paclitaxel in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer: SNIPER Study (ID 9803)
09:30 - 09:30 | Author(s): Tomoya Kawaguchi
- Abstract
Background:
Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-bound formulation of paclitaxel. This single-arm, phase II trial evaluated nab-paclitaxel monotherapy in pretreated patients with advanced non-small cell lung cancer (NSCLC).
Method:
In this multicentre, single arm phase II trial, we enrolled patients with advanced NSCLC who had previously treated more than one chemotherapy regimen. Patients received nab-paclitaxel 80 mg/m[2] days 1, 8, and 15 (21-day cycle). The primary endpoint was investigator-assessed overall response rate (ORR); secondary endpoints included overall survival (OS), progression-free survival (PFS), the disease control rate (DCR), and safety. The planned enrollment was 30 patients by Simon 2-stage minimax design.
Result:
We enrolled 30 patients. We analyzed endpoints about initially enrolled 24 cases that were available for the evaluation now. Sixty-three % of patients had previous treatment more than 2 regimens. The ORR and DCR were 25% (95% CI 8-42%) and 75%, respectively. Median PFS and OS were 5.8 months and 9.8 months, respectively. No new safety signals were reported; the most common grade ≥3 adverse events included neutropenia (54%), leukopenia (9%), and infection (13%).
Conclusion:
In patients with heavily advanced NSCLC, nab-paclitaxel demonstrated promising antitumor activity; further assessment of nab-paclitaxel monotherapy in this population of patients is supported.
