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S. Watanabe
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OA10 - EGFR Mutations (ID 382)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
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OA10.02 - Association of Variations in HLA-Class II and Other Loci with Susceptibility to EGFR-Mutated Lung Adenocarcinoma (ID 4192)
11:00 - 12:30 | Author(s): S. Watanabe
- Abstract
- Presentation
Background:
Lung adenocarcinoma (LADC) driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Understanding the genetic factors underlying such LADC is required to elucidate disease etiology and to identify effective methods of prevention.
Methods:
We investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls.
Results:
Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2, HLA-class II), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA-class II at 6p21.32 and 6p21.1 (FOXP4) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma (Shiraishi et al., Nature Communications, 2016, in press).
Conclusion:
This study indicates that multiple genetic factors, including an immunologic one, underlie the risk of lung adenocarcinomas with EGFR mutations.
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P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.05-051 - Safety and Compliance Data of the Phase III Study of Adjuvant Chemotherapy in Completely Resected P-Stage I Non Small Cell Lung Cancer: JCOG0707 (ID 3877)
14:30 - 15:45 | Author(s): S. Watanabe
- Abstract
Background:
Post-operative UFT (tegafur/uracil) has been shown to prolong survival of Japanese patients (pts) with completely resected, pathological (p-) stage I (T1> 2 cm) non small cell lung cancer (NSCLC). This trial aimed at estimating the efficacy of S-1 (tegafur/gimeracil/oteracil) compared to UFT as adjuvant therapy in this population.
Methods:
Eligible pts had undergone complete resection with lymph node dissection for p-stage I (T1-2N0M0, T1> 2 cm, by 5[th] Edition UICC TNM) NSCLC, within 56 days of enrollment. Pts were randomized to receive either oral UFT 250mg/M2/d for 2 years (Arm A), or oral S-1 80mg/M2/d for 2 weeks followed by 1 week of rest, for 1 year (Arm B). The initial primary endpoint was overall survival (OS). Based upon the results of monitoring in Jun. 2013, which showed the combined OS of the 2 arms better than expected (4-year OS of 91.6% vs. presumed 5-year OS of 70-76.5%), the study was judged to be underpowered. The study protocol was amended so that the primary endpoint was relapse-free survival (RFS). With a calculated sample size of 960, this study would detect the superiority of Arm B over Arm A with power 79% and a one-sided type I error of 0.05, assuming the 5-year RFS of 75% in Arm A and the hazard ratio of 0.75.
Results:
From Nov. 2008 to Dec. 2013, 963 pts were enrolled: median age 66 (range: 33 to 80), male 58%, adenocarcinoma 80%, p-T1/T2 46%/54%. Only 2 pts received pneumonectomy. All pts had completed protocol therapy. >Grade 3 toxicities (hematologic/nonhematologic) were observed in 15.9 (1.5/14.7) % in Arm A, and in 14.6 (3.6/11.9) % in Arm B, respectively. In Arm A, 59.5% of the pts completed protocol therapy, and 70.7% received UFT for >1 year, which was comparable to prior studies. In Arm B, 54.7% completed protocol therapy, and 69.9% received S-1 for > 6 months. There were 4 cases of on-protocol deaths, probably of cardio-vascular origin: 1 in Arm A and 3 in Arm B. Based on the 2[nd] interim analysis in Sep. 2015, the data and safety monitoring committee recommended the follow-up of pts without unmasking of treatment arms. Estimated combined 2-year OS and RFS were 97.3% and 89.6%, respectively.
Conclusion:
Both post-operative adjuvant therapies were feasible, with similar compliances. Main results will be available in 2019.
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-006 - Prognostic Impact of Tumor Spread through Air Spaces in Limited Resection for pStage I Lung Cancer (ID 4377)
14:30 - 15:45 | Author(s): S. Watanabe
- Abstract
Background:
Tumor spread through air space (STAS) is proposed as a new factor of lung cancer invasion, according to the new World Health Organization (WHO) classification. The aim of this study is to elucidate the prognostic impact and conduct a histopathological evaluation of STAS in primary lung cancer patients who underwent limited resection.
Methods:
We retrospectively collected 508 samples from p-Stage I primary lung cancer patients who underwent limited resection between 2004 and 2013. Hematoxylin and eosin stained tumor slides were reviewed to evaluate pathological features, including the presence or absence of STAS, and the morphological pattern in cases with STAS. We defined the pattern of STAS as single cell (SG), small cluster (SM), or large cluster (LG). Clinicopathological characteristics and patient outcome data were collected from medical records. SPSS statistical software (IBM Corporation, Somers, NY, USA) was used for statistical analysis.
Results:
Histological diagnoses were 440 adenocarcinomas (Ad) (including 107 Adenocarcinoma in situ and 144 Minimally invasive adenocarcinoma), 44 squamous cell carcinomas (Sq), and 24 other types of cancer. Seventy-six cases (15.0%: 60 Ad, 9 Sq, and 7 other types of cancer) were positive for STAS. The morphological STAS patterns were 12 SG, 45 SM, and 19 LG, respectively. There was no significant relationship between recurrence rate and morphological STAS pattern. The STAS-positive group was associated with the presence of micropapillary and/or solid components in Ad, and with lymphovascular and pleural invasion, compared to the STAS-negative group (p < 0.01). The median follow-up was 51 months. Eight local recurrences (1.6%), 16 locoregional (lung parenchyma, hilum, mediastinum) recurrences (3.1%), and 10 distant recurrences (2.0%) were recorded. In multivariate analysis, the risk of local (hazard ratio [HR]: 12.75; p < 0.01) and locoregional (HR: 4.12; p = 0.01) recurrence was significantly higher in the STAS-positive group than in the STAS-negative group. However, in a multivariate Cox model the presence of STAS was not associated with distant recurrence (p = 0.58).
Conclusion:
Our results indicated that the presence of STAS is a significant risk factor for local and locoregional recurrence, but not distant recurrence, in p-Stage I lung cancer following limited resection.
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P3.01-015 - Prognostic Impact of Histologic Invasion Factors in Pulmonary Adenocarcinoma, with Particular Focus on the Pattern of Architectural Remodeling (ID 4975)
14:30 - 15:45 | Author(s): S. Watanabe
- Abstract
Background:
In the 2015 WHO classification, histologic factors that are associated with invasion in primary lung adenocarcinoma (AdCa) include the presence of non-lepidic histologic subtypes (invasive subtypes) and the presence of cancer-associated myofibroblasts (CAFs). The prognostic significance of CAFs in combination with each invasive subtype has not been well assessed. We conducted this study to clarify the prognostic impact of CAFs in the absence of architectural remodeling.
Methods:
We retrospectively collected data and re-evaluated samples from 1052 patients with pathological stage 0 or IA pulmonary AdCa who underwent complete resection at our hospital between 2007 and 2012. HE and elastica van Gieson stains were used for histological evaluation. We defined two invasive subtypes: those with (INV-1) and without (INV-2) architectural remodeling of lung parenchyma. The postoperative recurrence of tumor was analyzed in each group.
Results:
Our reviewed diagnoses were 172 Stage 0 and 880 Stage IA AdCa. Of the 880 stage IA cases, 706 (80.2%) and 174 (19.8%) were categorized as INV-1 and INV-2, respectively. CAFs were observed in all cases in the INV-2 group, but were not always present in the INV-1 group. In the INV-2 group, the median diameter of the invasive component was 6 mm (range: 1-16), the median postoperative follow-up period was 60 months (range: 2-105), and none of the cases developed recurrence. In the INV-1 group, the median postoperative follow-up period was 55 months (range: 1-104) and the estimated 5-year recurrence-free probability by the Kaplan-Meier method was 93.0%. All cases with postoperative recurrence were categorized in the INV-1 group.
Conclusion:
The INV-2 group AdCa had a low risk of recurrence. These findings suggest that certain subtypes of invasive AdCa, which are classifiable based on the architectural remodeling pattern and the presence of CAF, can be considered to have a good prognosis.
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SC02 - Multifocal Lung Cancer (ID 326)
- Event: WCLC 2016
- Type: Science Session
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:G. Veronesi, S. Cicenas
- Coordinates: 12/05/2016, 11:00 - 12:30, Strauss 1
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SC02.03 - Surgery for Ground Glass Opacity: Sublobar Resection? (ID 6606)
11:00 - 12:30 | Author(s): S. Watanabe
- Abstract
- Presentation
Abstract:
History of standard surgical procedure for lung cancer In 1933, Graham reported the first successful pneumonectomy for a lung cancer patient, who survived for 18 years after surgery. In 1951, Cahan suggested that pneumonectomy with regional lymph node dissection should be a routine procedure for lung cancer in 1951. Then in 1960, Cahan reported the first 48 cases that successfully underwent lobectomy with regional lymph node dissection, which was called “radical lobectomy.” Since then, this procedure was universally accepted and has remained a standard surgery for lung cancer. As for sublobar resection, segmentectomy was initially used for the resection of localized bronchiectasis as reported by Churchill and Belsey (1939). In 1973, Jensik reported their 15-year successful experience of segmentectomy for lung cancer patients. However, the use of sublobar resection as definitive management of NSCLC has been a controversial issue. Lung Cancer Study Group (LCSG) (1995) conducted the only randomized trial comparing sublobar resection with lobectomy for stage IA NSCLC patients. They observed a 75% increase in recurrence and a 50% increase in cancer death in the patients undergoing sublobar resection, compared to those in the patients undergoing lobectomy. This is the reason why lobectomy has remained a standard lung cancer surgery for a half century since Cahn’s successful report in 1960. However, recently, we encounter many patients with the subsolid nodule、and a certain percentage of those patients are multifocal lesion. The significance and role of sublobar resection for subsolid tumor have become importanat so far. Controversies in sublobar resection for patients with small-sized NSCLC Sublobar resection is a lung parenchyma-preserving surgery with limited nodal dissection. However, even small-sized lung cancer less than 2 cm in size shows hilar and mediastinal nodal disease with an incidence of more than 20%. Although positron emission tomography (PET) is considered to be the most sensitive and accurate investigation for screening of lymph node involvement, with a sensitivity of 79 to 85% and specificity of 90 to 91% in a meta-analysis, the assessment of nodal status by PET is not reliable in patients with microscopic nodal metastasis. Riquet (1989) reported that lung cancer metastasizes so easily to the mediastinum that selection of the patients for limited surgery should be discussed carefully. Furthermore, lung cancer has a phenomenon termed “skip metastasis” consisting of N2 disease without N1 involvement with the incidence of 20-38% in N2 patients. Therefore, lobectomy with hilar and mediastinal lymph node dissection is considered to be a basic standard procedure for lung cancer. Differences in survival between sublobar resection and lobectomy However, with the recent development of the CT scanner, the number of very early-stage lung cancer showing ground-grass opacity (GGO) on CT is rising as well, and a new therapeutic strategy for nodal dissection has been required. Proposals of sublobar resection for small-size lung cancer less than 2 cm have been undertaken in some previous reports. Many retrospective studies of sublobar resection have already been undertaken for stage IA NSCLC patients. Regarding surgery for compromised stage IA patients, Hoffmann (1980), Landreneau (1997) and Campione (2004) showed no significant survival difference between sublobar resection and lobectomy group. Okada (2001) and Koike (2003) conducted the comparative study between intentional sublobar resection and standard lobectomy in patients with tumors 20mm or less in diameter. They showed no significant difference in survival between two groups and suggested that sublobar resection was acceptable operation for small-sized lung cancer. Nakamura (2005) reported the results of meta-analysis of 14 comparative studies showing survival difference between lobectomy and sublobar resection. He showed survival after lobectomy was slightly better at 1, 3, and 5 years, but the differences were not significant. Therefore, lobectomy with mediastinal dissection could be an excessive resection for selected patients with early lesion. Lobectomy, however, still remains to be a standard procedure for most patients with lung cancer, simply because there has been no universally accepted guidelines for conducting sublobar resection in the clinical settings. We should wait the final results of clinical trials shown in the following chapter. Clinical trials regarding sublobar resection vs. lobectomy and future perspective Japan Clinical Oncology Group (JCOG) has conducted a cohort study (JCOG0201) evaluating correlation between radiological and pathological findings in stage I adenocarcinomas. With pathologic non-invasive adenocarcinoma defined as those with no lymph node metastasis or vessel invasion, radiological non-invasive lung adenocarcinoma was defined as those with a consolidated maximum tumour diameter to tumour diameter ratio (C/T ratio) of less than 0.5. Currently, a prospective, randomized, multiinstitutional phase III trial for small-sized (<=2 cm) lung cancer patients is being conducted by Cancer and Leukemia Group B (CALGB140503) to determine the effectiveness of an intentional sublobar resection for small-sized peripheral tumors. Similar phase III study is also being conducted by JCOG (JCOG0802). JCOG has already accumulated planned number of patients and now following the patients. JCOG is also conducting other two prospective multiinstitutional phase II trials regarding the sublobar resection for GGO-dominant type tumors. One is JCOG0802, wide wedge resection or segmentectomy for non-solid GGO lesion less than 2cm, and the other is JCOG1211, segmentectomy for part-solid GGO lesion with less than 50% solid part inside and 2.1-3.0 cm in tumor diameter. Since the clear evidence regarding the survival benefit of sublobar resection for lung cancer patient is lacking so far, lobectomy should be an appropriate therapy for medically operable lung cancer patient at the moment. Abovementioned randomized trials will clearly define the role of sublobar resection in patients with stage I patients. As the number of early-stage peripheral lung cancers is increasing, and a certain number of patients are with multifocal small lesion, the surgical procedure for lung cancer should be tailored to each case by considering CT findings.
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