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S. Miyoshi
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-071 - Detection of Multiple Low-Frequency Mutations by Molecular-Barcode Sequencing (ID 4554)
14:30 - 14:30 | Author(s): S. Miyoshi
- Abstract
Background:
Recent advantage of next-generation sequencing (NGS) in the field of cancer genome research has revealed extreme levels of genetic heterogeneity, suggesting the major roles of subclonal mutations in cancer relapse and in rapid emergence of acquired resistance. Unlike inherited mutations, somatic variants often occur at low allele frequencies that require sensitive methods for detection. Based on the results using another highly sensitive method, such as digital PCR, the study of cancer subclones requires to detect mutations that are present in <1% frequency, however, such a level of resolution cannot be obtained by conventional NGS approaches. In the current study, we performed molecular-barcode sequencing for primary lung adenocarcinoma cases in order to analyze mutations with <1% low frequency.
Methods:
Fresh frozen tumor samples from 58 primary lung adenocarcinoma patients whose tumors previously tested positive for EGFR by conventional method (the PNA-LNA PCR clamp method) were collected. All samples were obtained from surgically resected specimen. We used HaloPlex HS method, which is a high sensitivity amplicon-based targeted sequencing method incorporating molecular barcodes in the DNA library, allowing for the identification of duplicate reads to significantly improve the base calling accuracy even at low allelic frequencies compared to conventional NGS methods. We used a panel designed for 47 cancer-related genes including EGFR, and sequenced data was obtained by using Illumina Miseq Reagent v3 (600 Cycle). Normal tissue samples were also sequenced for threshold adjustment.
Results:
Out of 58 samples, EGFR ‘major’ mutation (L858R, Exon19 deletion, G719A/S, T790M) profiles of 57 samples by molecular-barcode sequencing corresponded to those by clinical method (98.3%). The mean coverage of EGFR major mutation was 3078 (243-8285), and the minimal detectable frequency was 0.45%. Of note, we could detect the minor frequency of T790M mutation in addition to the major frequency of L858R mutation, at the allele frequency of 1.92% (20/1042) for T790M and 10.62% (155/1459) for L858R mutation, respectively. Minor genetic alterations, except major mutation, in EGFR were detected in 82.8% (48/58) cases, and the mean number was 2.3 (0-11). These results suggest the clinical applicability of this method.
Conclusion:
We could demonstrate good concordance rate between clinical examination and molecular barcode sequencing. Minor genetic alterations in EGFR were detected in 82.8% (48/58) cases. Further investigations are warranted to establish the confident detection of subclonal mutations with low frequency.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-032 - Impact of Preoperative Serum Anti-60S Ribosomal Protein L29 Levels on Prognosis in Patients Who Underwent Surgery for Non-Small Cell Lung Cancer (ID 4883)
14:30 - 14:30 | Author(s): S. Miyoshi
- Abstract
Background:
Ribosome is a subcellular organelle, which serves as the site of biological protein synthesis. Ribosomal protein L29 (RPL29) is one of the proteins composing ribosome, and it expresses in cell surface as well as in cytoplasm, especially showing its high expression in cancer cells.
Methods:
We retrospectively reviewed 92 patients who underwent surgical resection for non-small cell lung cancer between June 2010 and January 2012. Preoperative serum anti-RPL29 levels were measured by the indirect enzyme-linked immunosorbent assay. The cut-off value was represented by the median of anti-RPL29 levels.
Results:
The patients consisted of 60 males and 32 females, and their average age was 68.7 years (range: 44-87 years). Adenocarcinoma was the most common subtype (n = 69), which was followed by squamous cell carcinoma (n = 13), adenosquamous cell carcinoma (n = 4), pleomorphic carcinoma (n =4), and large cell carcinoma (n = 2). Postoperative pathological stage consisted of stage IA (n = 28), IB (n = 28), IIA (n = 11), IIB (n = 2), and IIIA (n = 23). EGFR activating mutations were found in 35 patients (32 adenocarcinomas, 2 adenosquamous cell carcinomas, and 1 pleomorphic carcinoma). The median of anti-RPL29 levels in 92 cases was 0.351. Three-year and five-year overall survival rate was 62.7% and 56.6%, respectively, in the patients whose serum anti-RPL29 level was less than the median, and 90.0% and 83.7%, respectively, in the patients with the median or more of anti-RPL29 levels (P = 0.005). In the multivariate Cox proportional hazard model, anti-RPL29 level being the median or more and pathological stage IA were identified as independent prognostic factors (P = 0.013 and P = 0.017, respectively).
Conclusion:
Serum anti-RPL29 levels may be a novel prognostic marker for non-small cell lung cancer.
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P2.02 - Poster Session with Presenters Present (ID 462)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 3
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.02-009 - Clinical Outcomes of Induction Chemoradiotherapy with High Dose Chest Radiation for Locally Advanced Non-Small Cell Lung Cancer Patients (ID 4362)
14:30 - 14:30 | Author(s): S. Miyoshi
- Abstract
Background:
In the treatment of patients with locally-advanced non-small cell lung cancer (LA-NSCLC), we usually apply chemoradiotheraphy (CRT) consisted of docetaxel and cisplatin with concurrent 40-60 Gy radiation therapy. The radiation dose of 60 Gy is generally planned in the case of definitive CRT. On the other hand, the radiation dose of 46 Gy is planned in the case of induction CRT, considering the safety of surgery. In the induction CRT, if the treatment response is poor and complete resection is supposed to be difficult, additional radiation is performed. In this study, we examined the safety and clinical outcome of lung resection after induction CRT using high-dose radiation in patients with LA-NSCLC.
Methods:
One hundred and eighteen patients with LA-NSCLC who underwent induction CRT followed by surgery between March 1999 and December 2014 in our hospital were reviewed. We categorized those patients into low-dose radiation group who received less than 60 Gy of radiation (n=105) and high-dose radiation group who received more than 60 Gy of radiation (n=13). We compared postoperative outcomes between these two groups applying match-paired analysis with using propensity score.
Results:
One hundred and eighteen cases consisted of 91 males and 27 females, and the average age was 60 years. Eleven patients had stage IIB disease, 73 patients had stage IIIA disease, and 34 patients had stage IIIB disease before CRT. The background between low-dose group and high-dose group was similar. There were no significant differences in the mortality (0.8% vs 0% in low-dose group and high-dose groups), the incidence of postoperative complication (57% vs 77%), and post-operative hospital days (median 22 vs 28 days) between each group. In addition, there were no significant differences in the 5-year OS rates (73% vs 77% in low-dose group and high-dose groups, p =0.66), and the 5-year DFS rates (56% vs 77%, p =0.11) between each group, even when we applied matched-paier analyses.
Conclusion:
This study showed that lung resection after induction CRT using high-dose radiation for LA-NSCLC patients had been performed safely with equivalent prognosis compared with that using low-dose radiation.
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P2.02-035 - The Advantage of Induction Chemoradiotherapy in Bronchoplastic Procedure for Non Small Cell Lung Cancer Accompanied with Central Disease Region (ID 5565)
14:30 - 14:30 | Author(s): S. Miyoshi
- Abstract
Background:
A bronchial sleeve lobectomy is a widely accepted procedure for enabling the pulmonary parenchyma to be spared. Trimodality therapy is one of therapeutic options for locally advanced non-small-cell lung cancer (NSCLC), though the negative effect of chemotherapy or radiotherapy on tissue healing is a concern. This study aimed to compare the clinical outcomes of pulmonary resection with bronchoplasty with or without prior induction chemoradiotherapy (CRT) and to investigate the feasibility of induction CRT in bronchoplastic procedure.
Methods:
The medical records of NSCLC patients who underwent surgery with bronchoplasty at our institution between January 1999 and September 2014 were reviewed. We compared the clinical outcomes of bronchoplasty with or without induction CRT.
Results:
A total of 58 NSCLC patients were the subjects of this study. Among them, 38 patients underwent primary surgery with bronchoplasty and 20 patients underwent surgery with bronchoplasty after induction CRT. The median patient age was 64 years (range: 31–81 years). The histological subtype was adenocarcinoma in 18 patients, squamous cell carcinoma in 39, large cell carcinoma in one. Of the 58 patients, seven patients had stage IA disease, five had stage IB disease, 10 had stage IIA disease, six had stage IIB disease, 24 had stage IIIA, and six had stage IIIB. Regarding the postoperative complications, there are no significant differences between the primary surgery group and the induction CRT group (P = 0.47). For the entire population, the 5-year overall survival (OS) rate was 69.9 %, and the 2-year recurrence-free survival (RFS) rate was 64.2 %. Even though the clinical stage was significantly higher in the induction CRT group than in the primary surgery group (P = 0.0006), no significant differences in OS and RFS rate were observed between the two groups. Regarding the intraoperative procedures, patients in the primary surgery group had a significantly higher rate of additional bronchial resection because of positive bronchial margin for cancer cell than those in the induction CRT group (P = 0.023).
Conclusion:
In bronchoplasty, additional resection of airway after intraoperative histological examination should be avoided to prevent tumor cell dissemination. Our experience suggests the possible advantage of induction CRT to ensure the surgical margin and indicates that surgery with bronchoplasty after induction CRT is a feasible procedure.
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P2.02-054 - Impact of Prognostic Nutrition Index for Induction Chemoradiotherapy Followed by Surgery in Locally Advanced Non-Small Lung Cancers (ID 4607)
14:30 - 14:30 | Author(s): S. Miyoshi
- Abstract
Background:
The preoperative nutritional and immunological statuses have an important impact in predicting the clinical outcome of surgery. Induction chemoradiotherapy (iCRT) followed by surgery is one of treatment options for locally advanced (LA) non-small cell lung cancers (NSCLCs) although there is a risk for increasing postoperative complications with protracted would healing. A prognostic nutritional index (PNI), calculated using serum albumin levels and peripheral lymphocyte count, has been used to predict the clinical outcome of various cancers including early stage NSLCCs but not LA-NSCLC after iCRT. In this study, we investigated the impact of PNI on clinical outcome of iCRT followed by surgery in the patients with LA-NSCLCs.
Methods:
During 2009 to 2014, 70 patients underwent iCRT followed by surgery in Okayama University Hospital. We retrospectively calculated the PNI at (1) pre-iCRT, (2) pre-operation (Ope), and (3) post-Ope (about one month later) and reviewed the medical records.
Results:
The median age was 63 years old (range 34 – 78) and 53 patients were male. Forty-three patients were adenocarcinomas and 24 were squamous cell carcinomas. Clinical stages were IIA (n =3), IIB (n = 6), IIIA (n = 44), IIIB (n = 15), and IV (n = 2). Main regimen of iCRT was CDDP / DOC with concurrent radiotherapy (46 gray). Treatment responses were partial response (n = 44), no change (n = 24), and progressive disease (n = 2). Lung resections were lobectomy (n = 66), bi-lobectomy (n = 6), and pneumonectomy (n = 2) and additional procedure such as combined resection was performed in 43 patients (61%). Pathological responses were Ef1 (n = 20), Ef2 (n = 29), and Ef3 (n = 21). The median values of PNI were significantly decreased during treatment course [50 (39 – 71) in pre-ICRT, 45 (31 – 58) in pre-Ope, and 41 (24 – 54)]. We defined the cutoff value of PNI as 45 based on previous reports. The patients with high PNI (more than 45) in pre-iCRT showed significantly better prognosis than those with low PNI (3 years overall survival rate, 85% in high PNI vs 53% in low PNI, P = 0.03).
Conclusion:
Pre-treatment nutritional and immunological statuses that were evaluated using PNI may affect clinical outcome of the patients who received the iCRT followed by surgery for LA-NSCLCs.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-121 - Targeting miR-200c/LIN28B Axis in Acquired EGFR-TKI Resistance Non-Small Cell Lung Cancer Cells Harboring EMT Features (ID 5677)
14:30 - 14:30 | Author(s): S. Miyoshi
- Abstract
Background:
MicroRNA (miR)-200 family members (miR-200s) are frequently silenced in advanced cancer and have been implicated in the process of epithelial-to-mesenchymal transition (EMT). We previously reported that miR-200s were silenced through promoter methylation in acquired EGFR-tyrosine kinase inhibitor (TKI) resistant non-small cell lung cancer (NSCLC) cells harboring EMT features. In this study, we examined the functional role of miR-200s in NSCLC cells and investigated the novel approach overcoming acquired EGFR-TKI resistance.
Methods:
We examined miR-200s expressions and promoter methylation statuses in 34 NSCLC cell lines. Then, we analyzed the altered pathway molecules associated with miR-200c statuses using publicly accessible database. Finally, we examined the antitumor effect targeting the molecules related to miR-200s expression in EGFR-TKI sensitive HCC4006 cells and acquired resistance cell line with EMT features HCC4006-GR cells.
Results:
In the analysis of NSCLC cell lines, miR-200s expression silenced cell lines showed each promoter methylation. There were significant correlations between miR-200c silencing and several oncogenic pathway alterations, including EMT-change and LIN28B overexpression, in database analysis. In addition, EGFR-wild type cell lines showed lower miR-200s expressions compared to EGFR-mutant cell lines. Introduction of miR-200c by using pre-miR-200c caused LIN28B suppression in HCC4006-GR cells. Interestingly, both introduction of miR-200c and knockdown of LIN28B showed antitumor effect in HCC4006-GR cells, whereas they were not effective in parental HCC4006.
Conclusion:
MiR-200c/LIN28B axis plays an important role in acquired resistance to EGFR-TKI and can be a therapeutic target overcoming drug resistance.
