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T. Eguchi
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ORAL 28 - T Cell Therapy for Lung Cancer (ID 132)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:P.S. Adusumilli, E. Smit
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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ORAL28.05 - Mesothelin and MUC16 (CA125) Are Antigen-Targets for CAR T-Cell Therapy in Primary and Metastatic Lung Adenocarcinoma (ID 3159)
16:45 - 18:15 | Author(s): T. Eguchi
- Abstract
Background:
Chimeric antigen receptor (CAR) T-cell therapy has shown durable remissions in hematological malignancies targeting cancer-antigen CD19. Ideal cancer-antigen targets for CAR T-cell therapy are antigens overexpressed on cancer cell-surface with limited expression in normal tissues, associated with tumor aggressiveness and expressed in a large cohort of patients. In our search for such candidate antigens in lung adenocarcinoma (ADC), we investigated the overexpression of Mesothelin (MSLN), MUC16 (CA125), and the combination of MSLN-MUC16 as the interaction of both antigens has been shown to play a role in tumor metastasis.
Methods:
In patients with stage I lung ADC (n = 912, 1995 - 2009), a tissue microarray consisting of 4 cores from each tumor and normal lung tissue was used to examine the antigen-expression characteristics, and their association with cumulative incidence of recurrence (CIR). Autologous metastatic tumor tissue was available from 36 patients. Differences in CIR between groups were tested using the Gray method (for univariate nonparametric analyses) and Fine and Gray model (for multivariate analyses).
Results:
MSLN and MUC16 were not expressed in normal lung tissue. In primary and metastatic lung ADC tumors, MSLN was expressed in 69% and 64%, MUC16 was expressed in 46% and 69%, both antigens were present in 50% and 33%, and either antigen were present in 33% and 49% respectively. On univariate analysis, patients with high MSLN expression had high risk of recurrence than low expression [5-year CIR, High: 25.1% vs Low: 17.6%, P = 0.017]. Patients with high MUC16 expression had high risk of recurrence than low expression [5-year CIR, High: 24.2% vs Low: 14.0%, P < 0.001]. Patients with high MUC16 and high MSLN had higher risk of recurrence than low expression [5-year CIR, High risk (High MUC16 and High MSLN): 27.6%, Intermediate risk (High MUC16 and Low MSLN): 24.2%, Low risk (Low MUC16): 13.6%, P < 0.001]. On multivariate analysis, increased MUC16-MSLN expression was associated with recurrence [Hazard ratio, 2.57 95% Confidence interval 1.41 – 4.68 P = 0.002], even after adjustment for currently known markers of lung ADC aggressiveness (gender, surgical procedure, stage, architectural grade and lymphatic invasion). High expression of MUC16 in the primary tumor was associated with high expression at recurrence sites.
Conclusion:
MSLN, MUC16 or a combination of expression of both antigens in patients with primary lung ADC is associated with increased risk of recurrence, a retained overexpression at metastatic sites in advanced lung ADC indicating that MUC16-MSLN expression is a marker of tumor aggressiveness. Expression in the majority of lung ADC patients imparting aggressiveness with no expression in normal lung provides the rationale to target MSLN and MUC16 for lung ADC CAR T-cell therapy.
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P3.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 214)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.03-010 - Usefulness of Vessel Sealing Devices in Thoracoscopic Lobectomy for Lung Cancer (ID 825)
09:30 - 17:00 | Author(s): T. Eguchi
- Abstract
Background:
Vessel sealing devices (VSD) are widely used for various surgical procedures. They are regarded as useful in thoracoscopic surgery, but few reports have substantiated this belief by comparison with non-use of VSD in human thoracoscopic lobectomy. Aiming to establish a simpler and safer thoracoscopic lobectomy, we examined the usefulness of VSDs.
Methods:
Primary lung cancer patients for whom a thoracoscopic lobectomy involving mediastinal lymph node dissection was planned in our department from April 2011 to June 2013 were recruited for the study. Patients were randomly allocated to a control group (n=15) or a VSD group (n=46), which constituted of three subgroups, namely, EnSeal (n=17), LigaSure (n=15), and Harmonic (n=14). The control group comprised of patients undergoing surgery solely with ligation and conventional electrocautery. EnSeal, LigaSure, and Harmonic were chosen because they are the 3 most popular disposable VSDs used in Japan. Primary endpoints were burst pressure of the pulmonary artery stump (measured using resected specimens), operative time, intraoperative blood loss, instances of endostapler use, intraoperative surgeon stress (assessed by visual analog scale), and postoperative drainage volume and duration. As a secondary objective, the individual VSD groups were also compared with each other.
Results:
The burst pressure of ligation-treated pulmonary artery stumps was higher than that of VSD-treated stumps (P<0.0001). The burst pressure of < 5-mm wide VSD-treated stumps was higher than that of ≥ 5 mm wide stumps (P=0.0359). However, burst pressure for all groups and all vessel diameters was sufficient to withstand physiological pulmonary artery pressure. The VSD group demonstrated reduced intraoperative blood loss (P=0.0174), surgeon stress (P=0.0001), postoperative drainage volume (P=0.0270), and shortened postoperative drainage duration (P=0.0330). Operative time and the instances of endostapler use did not significantly differ. Comparison between each of the VSD groups revealed no significant differences. None of the patients experienced serious perioperative complications or died because of surgery.
Conclusion:
VSD is simple and safe to use in thoracoscopic lobectomy involving mediastinal lymph node dissection for primary lung cancer. Further, none of the VSDs used in this study presented any observable differences in quality that could lead to clinical problems.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-092 - HNF4α Is a Marker for Invasive Mucinous Adenocarcinoma (IMA) and a Prognostic Factor in Stage I Lung Adenocarcinoma (LADC) (ID 3066)
09:30 - 17:00 | Author(s): T. Eguchi
- Abstract
Background:
According to the 2015 WHO classification, invasive LADC with prominent apical intra-cytoplasmic mucin and small basally oriented nuclei, formerly referred to as mucinous bronchioloalveolar carcinoma, is classified as IMA. Hepatocyte nuclear factor 4 alpha (HNF4α) is a recently recognized marker for IMA although it is also infrequently positive for other subtypes of LADC. However, the prognostic significance of HNF4α is not known. We investigated the frequency of HNF4α expression in IMA as well as non-IMA subtypes, and the prognostic significance of HNF4α in Stage I LADC.
Methods:
Slides from patients with therapy-naive, surgically resected solitary stage I LADC (1995-2009) were subtyped according to the 2015 WHO classification. Tissue microarrays were constructed from each tumor (n=793), and stained for HNF4α. HNF4α expression intensity (0-3) and distribution (1, 1%-50%; 2, 51%-100%) were summed into a total score (0-5) and dichotomized as negative (score <2) or positive (score ≥2). Comparisons were made with TTF-1 expression. Recurrence-free probability (RFP) was estimated using the Kaplan-Meier method, and multivariate analyses were performed using the Cox proportional hazards model.
Results:
32 cases were identified as IMA. Of all LADC, HNF4α was positive in 68 cases (9%) including72% (n = 23) of IMA, 6% (n = 45) of tumors with non-IMA subtypes (P < 0.001). Among non-IMA subtypes, HNF4α was positive in 6% of lepidic, 4% of papillary, 2% of micropapillary, 7% of solid, and 29% of colloid tumors. HNF4α was positive in 12% of KRAS mutant tumors while it was negative in all EGFR mutant tumors (P < 0.001). HNF4α was more frequently positive in TTF-1 negative tumors (40%) than TTF-1 positive tumors (5%; P < 0.001). The RFP for patients with HNF4α-positive tumors was significantly lower than that for patients with HNF4α-negative tumors (P = 0.002) in the entire cohort. This finding was confirmed in subgroup analysis of patients with non-IMA subtypes (P = 0.009). In multivariate analysis, HNF4α was an independent prognostic factor for recurrence (HR=1.61, 95%CI =1.27-2.02, p<0.001).
Conclusion:
HNF4α expression was significantly associated with IMA histology, negative EGFR mutation status, and TTF-1 negativity. Furthermore HNF4α was also expressed infrequently in non-IMA subtypes, however in these patients it was a significant prognostic factor.
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P3.04-118 - Expression of TS and DPD in Primary Lung Cancer (ID 287)
09:30 - 17:00 | Author(s): T. Eguchi
- Abstract
Background:
Chemotherapy with 5-fluorouracil (5-FU) preparations is widely used to treat gastrointestinal cancer, head and neck cancer, and breast cancer. 5-FU acts by inhibiting thymidylate synthase (TS), the rate-controlling enzyme of pyrimidine synthesis, and its anticancer activity is related to the rate of TS inhibition in gastrointestinal cancer and other tumors. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for the catabolism and inactivation 5-FU. As one biochemical modulation strategy, uracil–tegafur (UFT) has been developed to improve the bioavailability of 5-FU by inhibiting DPD. Expression levels of TS and DPD in resected lung cancer samples are generally determined quantitatively by reverse-transcription polymerase chain reaction (RT-PCR) or qualitatively by immunohistochemical analysis. However, no study has employed enzyme-linked immunosorbent assay (ELISA) to measure TS and DPD expression in lung cancer, although this technique is often used for gastrointestinal, colorectal, and breast cancers.
Methods:
From April 2004 through December 2007, we studied tissue samples from 168 of 280 patients with primary lung cancer in which both TS and DPD could be measured. TS and DPD in normal and tumor tissues were quantified by ELISA and compared according to expression level, gender, histological type, and clinicopathological characteristics. Patient Characteristics: Of the 168 patients, 110 were men (65.4%), and 58 were women (34.6%). The median age was 69.6 (range, 35-89) years; 107 patients were former or current smokers and 61 were nonsmokers.The pathologic disease stage was IA in 59 patients, IB in 34, IIA in 8, IIB in 23, IIIA in 33, IIIB in 7, and IV in 4. The patients with stage IV disease had brain metastasis. The most common histological type was adenocarcinoma (107 cases), followed by squamous cell carcinoma (39), adenosquamous carcinoma (2), large cell carcinoma (9), small cell carcinoma (5), pleomorphic carcinoma (3), and carcinoid (3).
Results:
Expression levels of TS and DPD were significantly higher in lung cancer tissue than in noncancerous tissue. As for patient characteristics, TS expression in tumors was significantly lower in women and nonsmokers. According to histological type, tumor TS expression was significantly lower in adenocarcinoma and squamous cell carcinoma than in other types of lung cancer, whereas DPD expression did not differ significantly among histological types. Median tumor TS expression was significantly lower in well-differentiated tumors than in moderately/poorly-differentiated tumors. Among patients with adenocarcinoma (n=107), median tumor TS expression was significantly lower in women and nonsmokers.
Conclusion:
The present study suggested that tumor TS and DPD levels are useful predictors of chemosensitivity to UFT in patients with primary lung cancer who receive postoperative adjuvant chemotherapy. The expression level of TS in tumors may be useful for selecting postoperative treatment for individual patients with lung cancer, particularly those who are women or nonsmokers or who have adenocarcinoma.
