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Shun-ichi Watanabe
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P1.05 - Early Stage NSCLC (ID 691)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.05-002 - Characteristics and Prognosis of Ground Glass Opacity Predominant Primary Lung Cancer Larger Than 3.0 Cm on Thin-Section Computed Tomography (ID 7396)
09:30 - 16:00 | Author(s): Shun-ichi Watanabe
- Abstract
Background:
The solid component size of lung cancer showing ground glass opacity (GGO) on thin-section computed tomography (TSCT) has been regarded as a more important preoperative prognostic indicator than the whole tumor size. Moreover, previous study revealed that radiological early lung adenocarcinoma which has an excellent prognosis could be defined as an adenocarcinoma 3.0 cm or less with consolidation to tumor ratio (CTR) of 0.5 or less on TSCT. However, the characteristics and the prognosis of lung cancer larger than 3.0 cm showing GGO remain unclear.
Method:
From January 2002 through June 2012, we retrospectively reviewed 3,735 consecutive patients with primary lung cancer, which underwent complete resection at our institution. We extracted 686 (18.4%) patients with lung cancer larger than 3.0 cm in diameter and evaluated their preoperative TSCT findings. In total, 160 (4.3%) lung cancers larger than 3.0 cm showing GGO were eligible for this analysis. We divided the 160 lesions into three types based on CTR; type A: 0
Result:
Type A, type B, and type C were found in 16 (10%), 37 (23%), and 107 (67%) lesions, respectively. Regarding the operative mode, all patients except for two patients underwent lobectomy. All patients except for one patient was diagnosed as having adenocarcinoma. Lymph node metastasis was seen in none of types A and B, in 34 (32%) lesions of type C. Lymphovascular invasion was seen in 73(68%) lesions of type C, 6 (16%) lesions of type B but not in type A. The median follow-up period was 68 (2-162) months. Recurrence was not observed in patients with type A and type B. The 5-year overall survival (OS) and disease free survival (DFS) rates were both 100% in type A, both 97.2% in type B, and 88.4%, 66.7% in type C, respectively. Patients with type C had a significantly worse prognosis than did those with the other types with respect to OS (p = 0.033) and DFS (p < 0.001).
Conclusion:
Tumors with type A and type B on TSCT showed an excellent prognosis with no lymph node metastasis. Therefore, GGO predominant lung cancer could be considered “early” lung cancer even if tumor size was larger than 3.0 cm in diameter.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-035 - PD-L1 IHC Test on Cytological Cell Block Specimen; Potential Utility and Practical Issues (ID 9018)
09:30 - 16:00 | Author(s): Shun-ichi Watanabe
- Abstract
Background:
PD-L1 IHC test is an important biomarker for predicting the response of the immune checkpoint inhibitor against the PD1/PD-L1 axis. The FFPE tissue sample is an only validated specimen used in the clinical study, although it is sometimes difficult to obtain an enough tissue sample in advanced stage patients. Cytology specimen is an expected candidate. In this study, we evaluated the PD-L1 IHC expression on cytology cell block specimen (CB) and compared to the corresponding formalin-fixed-paraffin-embedded tumor tissue sample (FFPE-T).
Method:
Nine primary lung cancer patients who have both surgical resected FFPE-T and pleural effusion CB were recruited. CB was prepared as following; pleural fluid was centrifuged to collect the cell pellet, then fixed in formalin and embedded in paraffin. PD-L1 expression was evaluated using two clones (DAKO PharmDx kit, 22C3 and 28-8). Three pathologists (two certified, one path-trainee) and one cytotechnologist reviewed the slides independently. The proportion score of tumor cell (TPS) was evaluated and divided into 2-tier (positive, negative for 28-8) and 3-tier (no, low, high expression for 22C3) categories, according to the manufactural protocols. The correlation between CB and FFPE-T and the inter-observer agreement (kappa value) were calculated.
Result:
All samples were acceptable for PD-L1 evaluation. FFPE-T resulted in 2 positive, 7 negative (28-8); 3 low and 6 no expression (22C3), respectively. CB resulted in 5 positive, 2 negative (28-8); 3 low and 6 no expression (22C3), respectively. The TPS and tiered-category of CB did not correlate to those of FFPE-T, statistically. The concordant rate of tiered-category between FFPE-T and CB resulted in 4/9 (45.4%) for both clones. It can be explained by the heterogeneity of PD-L1 expression. The TPS and category judgment of two tests (28-8 and 22C3) within each observer were statistically correlated (R=0.588-0.951, p-value <0.001). The kappa value of the inter-observer agreement varied from 0.18 to 1.0, depending on the experience and education. Two certified pathologists reached moderate (kappa=0.59 for 28-8) to high (1.0 for 22C3) agreement on CB, but low (0.05 and 0.14) on FFPE-T. The kappa value between certified pathologist and path-trainee/ cytotechnologist was 0.6/ <0.01 for FFPE-T, and 0.18/0.57 for CB, respectively. These results seem to be influenced by the recognition of appropriate target tumor cells.
Conclusion:
Our study suggested that the properly processed cytology sample has a potential clinical utility for PD-L1 evaluation. The difficulty of target cell recognition on cytology specimen seems to be one of the critical issues of standardization.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-035 - Mutational Signatures and Their Association with Clinicopathological Features in Lung Adenocarcinoma of Smokers (ID 8623)
09:30 - 16:00 | Author(s): Shun-ichi Watanabe
- Abstract
Background:
Lung adenocarcinoma (LADC) harboring druggable driver oncogene such as EGFR mutation and ALK fusion can be treated with molecular-targeted drugs. These oncogene aberrations are frequently observed in LADCs of never-smoker, while LADCs of smokers often lack such druggable oncogene aberrations. Therefore, understanding mutation profile of LADCs of smokers is required to improve precision lung cancer medicine..
Method:
We analyzed mutational signatures of somatic mutations in 373 LADCs (smoker 220 cases; 59%, never-smoker 153 cases; 31%) of Japanese using whole exome sequencing data. Four mutational signatures were identified by non-negative matrix factorization and logistic regression analysis. We are now analyzing significantly mutated gene (SMG)s by MutSigCV1.5 of LADCs of smokers and associations of each signature with clinicopathological factors including histological subtype and prognosis.
Result:
Indel mutations as well as well-characterized C>A mutations were defined as mutational event more prevalent in LADC of ever-smokers than in never-smokers (P=8.76E-15 and P=0.000417 respectively). A novel set of genes were identified as a main target for indel mutations (7.4%; 22 of 296 samples), and their mutations were significantly associated with smoking and with UIP co-occurrence in their lung (P=0.0068 and P=0.037, respectively). Indel mutations in 3’-UTRs of these genes caused specific reduction in mutant transcripts, while those in coding region caused truncation of polypeptide.
Conclusion:
A novel gene set including those in 3’-UTR, would contribute to LADC development in smokers and associated with usual interstitial pneumonia, by promoting undifferentiation of tumor cells.
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P3.16 - Surgery (ID 732)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.16-025 - Tumor Doubling Time Is the Most Important Predictor of Survival and Pathological Diagnosis in Metachronous Lung Cancer (ID 9101)
09:30 - 16:00 | Author(s): Shun-ichi Watanabe
- Abstract
Background:
Good prognosis following surgery for metachronous second primary lung cancer has been reported. However, distinguishing pulmonary metastasis from metachronous second primary lung cancer is difficult.
Method:
Patients who underwent multiple pulmonary resections for metachronous lung cancer at our institution between 2000 and 2014 were retrospectively analyzed. Metachronous lung cancer was defined as non-small cell cancer regardless of disease-free interval or histologic concordance.
Result:
The retrospective chart review identified 86 patients. The median patient age at the time of second resection was 72 years, and 53 out of 86 patients (62%) were male. The median time interval between first and second resection was 1540 days. The mean tumor size was 19 ± 8 mm, the mean tumor doubling time was 316 ± 305 days, and 71 out of 86 patients (83%) had concordant histology. Upon postoperative pathological examination, the metachronous lung cancer was diagnosed as second primary lung cancer in 72 patients (84%), and pulmonary metastasis in 4 patients (5%). In the remaining 10 patients (12%), second primary lung cancer was indistinguishable from pulmonary metastasis. In second primary lung cancer, pulmonary metastasis, and indistinguishable tumors, the 5-year overall survival rates were 82%, 50%, and 53%, respectively. Factors significantly associated with improved overall survival included: tumor doubling time >180 days; pathological diagnosis of second primary lung cancer; pathological stage IA; >2 year interval between first and second surgery; and a consolidation/tumor ratio of ≤0.5. A tumor doubling time of >180 days was significantly associated with pathological diagnosis of second primary lung cancer. Using multivariate analysis, we also found that tumor doubling time >180 days was the only independent predictor of superior overall survival.
Conclusion:
This study found that tumor doubling time is the most important preoperative predictor of survival and pathological diagnosis of second primary lung cancer in metachronous lung cancer. The classic criteria for the diagnosis of a metachronous primary lung cancer were defined by Martini and Melamed. A tumor was considered to be metachronous primary lung cancer if the histologic type was discordant, or if the disease-free interval was at least 2 years for tumors with a histologic type similar to that of the primary cancer. However, due to the rising incidence of adenocarcinoma, earlier detection by computed tomography, and later recurrence due to adjuvant chemotherapy, Martini and Melamed’s criteria should be modified. We propose that tumor doubling time of >180 days should be a new criterion among Martini and Melamed’s criteria.
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PL 01 - Prevention, Screening, and Management of Screen-Detected Lung Cancer (ID 586)
- Event: WCLC 2017
- Type: Plenary Session
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:Michael Boyer, Matthijs Oudkerk
- Coordinates: 10/16/2017, 08:15 - 09:45, Plenary Hall (Exhibit Hall D)
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PL 01.04 - What is the Optimal Management of Screen-Detected Lung Cancers (ID 7840)
08:15 - 09:45 | Presenting Author(s): Shun-ichi Watanabe
- Abstract
- Presentation
Abstract:
Introduction With the recent development of the CT scanner, the number of CT screen-detected early-stage lung cancer showing ground-grass opacity (GGO) is rising. Therefore a new optimal therapeutic strategy for pulmonary resection for screen-detected lung cancer has been required. History of standard surgical procedure for lung cancer Cahan (1960) 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). Jensik (1973) 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. 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 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 Proposals of sublobar resection for clinical stage IA small-sized lung cancer less than 2 cm have been undertaken in some previous reports. Although these were non-randomized study, Okada (2001) and Koike (2003) conducted the comparative study between intentional sublobar resection and standard lobectomy in patients with tumors 20 mm 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. The significance and role of sublobar resection for subsolid tumor have become important so far. Clinical trials regarding sublobar resection vs. lobectomy 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 tumor diameter to tumor diameter ratio (C/T ratio) of less than 0.5 (9). Currently, a prospective, randomized, multi-institutional 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 (JCOG0802) is also being conducted, comparing lobectomy vs. segmentectomy for small-sized tumor with more than 0.5 C/T ratio. JCOG has already accumulated planned number of patients and now following the patients. JCOG is also conducting other two prospective multi-institutional phase II trials regarding the sublobar resection for GGO-dominant type tumors. One is JCOG0804, wide wedge resection for non-solid GGO lesion less than 2cm, and the other is JCOG1211, segmentectomy for part-solid GGO lesion with less than 0.5 C/T ratio and 2.1-3.0 cm in tumor diameter. Sublobar resection: anatomic or non-anatomic? No large-scale randomized trial comparing AS with non-anatomic WR, which is technically much easier than AS, for small-sized NSCLC has been conducted so far. Despite the fact that patients undergoing AS were more likely to have nodal sampling/dissection, and more LNs retrieved than patients undergoing WR in the present study, Altoki (2017) suggested that it did not lead to an improvement in survival. This is consistent with the results of the ACOSOG Z0030 trial comparing lymph node sampling with systematic nodal dissection in patients with T1-2 N0-1 NSCLC with no difference in survival between the two groups. These findings are of interest since data from the LCSG randomized trial showed that locoregional recurrence after WR was two-fold higher than that after AS. The results that AS should be the preferred option for SR were supported by recent large population-based studies suggesting. Smith (2013) reported the results of evaluating a large population Surveillance, Epidemiology and End Result-Medicare registry (SEER) database. They found that WR were associated with inferior survival compared to AS. However, advantage of AS over WR in the SEER database is probably due to different patient selection criteria as well as inadequate wedge resections with sub-optimal resection margins and insufficient or no nodal assessment. Whether WR and AS were comparable oncologic procedures for cT1N0M0 NSCLC patients or not has been still controversial issue so far. Conclusions 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 choice of surgical procedure, that is, lobectomy, AS or WR, should be tailored to each case in the future.
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