Virtual Library
Start Your Search
S.J. Heo
Author of
-
+
P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P1.04-101 - Utility of Patient-Derived Cell Line Models Using Conditional Reprogramming for in Vitro Pharmacogenomics Platform (ID 963)
09:30 - 09:30 | Author(s): S.J. Heo
- Abstract
Background:
To evaluate the potential of conditional reprogrammed cells (CRCs) established from biopsy or effusion samples of advanced non-small cell lung cancer (NSCLC) for in vitro pharmacologic screen and identification of drug resistance mechanisms.
Methods:
A total of 48 tumor specimens obtained from 46 patients with NSCLC were cultured with irradiated fibroblast feeder cells and Rho kinase inhibitor (Y-27632) to induce tumor cells to proliferate indefinitely. The cell lines established from patients harboring EGFR mutation or other druggable oncogenes were subjected to genetic analyses and pharmacologic screen. Corresponding tumor cells were injected into nude mice to test for tumorigenicity and efficacy of targeted agents in vivo.
Results:
Twenty one male patients and twenty five female patients were assessed for establishment of CRC. Adenocarcinoma was the most frequent histologic type (84.7%). There were 21 patients (46%) who harbored an active EGFR mutation. There were four patients with ALK fusion and five with ROS1 fusion. Twenty-six patients experienced disease progressed while on treatment with EGFR (20), ALK (2) or ROS1 (4) tyrosine kinase inhibitors. Tumor cells came from primary or distant metastases in 48% and 52%, respectively. Thirty one (65%) samples were obtained by tumor biopsy and 17 from malignant pleural effusion. Nine CRC model were successfully established (18.7%, 9/48). The successful growth was not dependent on the clinicopathologic characteristics. Both cells from pleural effusion (4 of 17) and biopsy (5 of 31) and adenocarcinoma (8 of 41) and squamous cell carcinoma (1 of 3) were successfully cultured. For biopsy samples, the success rate of cells obtained from primary lung lesion was 21.7% (5 of 23) and cells from metastatic site outside lung was 0% (0 of 8) (P = 0.3). For effusion samples, volume of effusion required for CRC was not significant factors for establishment (success vs. failure cases: mean volume 500 ml vs. 267 ml). The genetic characteristics of patients with non-squamous cell carcinoma did not affect the success rate of CRC (EGFR mutation, 4 of 21; ALK translocation, 0 of 4; ROS1 translocation, 2 of 5; wild or unknown, 2 of 15). Two xenograft models with CRC were successfully established and passaged to maintain tumor in vivo.
Conclusion:
The CRC models derived from NSCLC patients provide useful in vitro platforms of preclinical studies evaluating novel targeted therapies and uncovering the drug resistance mechanisms.
-
+
P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
-
+
P2.01-064 - A Randomized Phase II Trial of ERCC1 and RRM1 Expression-Based Chemotherapy versus Docetaxel/Carboplatin in Advanced Non-Small Cell Lung Cancer (ID 976)
09:30 - 09:30 | Author(s): S.J. Heo
- Abstract
Background:
Platinum-based doublet chemotherapy is still mainstay in treatment of advanced non-small-cell lung cancer (NSCLC). There was no molecular determinant for guiding platinum-based chemotherapy. Excision repair cross-complementing group 1 gene (ERCC1) is important for platinum-induced DNA adduct repair and ribonucleotide reductase subunit 1 (RRM1) is crucial for nucleotide metabolism and has been known for the dominant molecular determinant of gemcitabine efficacy. We assessed whether selection of first-line chemotherapy based on ERCC1 and RRM1 mRNA expression levels would improve clinical outcomes in patients with advanced NSCLC.
Methods:
Eligible patients were randomly assigned 1:1 to experimental arm and control arm. The experimental arm consisted of gemcitabine/carboplatin (GC) if ERCC1 and RRM1 were low, gemcitabine/vinorelbine (GV) if ERCC1 was high and RRM1 was low, docetaxel/carboplatin (DC) if ERCC1 was low and RRM1 was high, and docetaxel/vinorelbine (DV) if both were high. In the control arm, patients received docetaxel/carboplatin (DC). All chemotherapy regimens were to be continued for maximum 4 cycles every 3 weeks or unacceptable toxicity. ERCC1 and RRM1 mRNA expression were measured by quantitative real-time PCR in formalin-fixed paraffin-embedded (FFPE) tissue. The trial was powered for an 80% improvement in overall response rate (ORR, P0=0.25, P1=0.45, α=0.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The study was prematurely terminated after the futility analysis of 42 PFS events, which showed a low conditional probability (conditional power=0.14) of a statistically significant outcome.
Results:
A total of 56 patients (n=26 in experimental arm, n=30 in control arm) were evaluable for efficacy and toxicity. Patient characteristics were well balanced in both groups. Majority of patients had adenocarcinoma histology (64.3%) and ECOG performance status 0 to 1 (96.4%). EGFR mutation was documented in 8 patients (4 in experimental arm, 4 in control arm). Among 26 patients in the experimental arm, mRNA expression of ERCC1 and RRM1 ranged from 0.18 to 2.81 (median, 0.69) and 0.22 to 16.65 (median, 0.66), respectively. Based on mRNA expression levels, 19 (73.1%) patients were assigned to GC, 0 (0.0%) to GV, 4 (15.4%) to DC, and 3 (11.5%) to VD. The median number of chemotherapy cycles delivered was 3.7 in experimental arm and 3.5 in control arm. The ORRs were 26.9% in experimental arm and 40.0% in control arm, which were not statistically significant (P=0.58). With a median follow-up of 30.1 months, median PFS was 4.6 months in experimental arm and 5.1 months in control arm (hazard ratio [HR] 1.27; 95% CI 0.69-2.31; P=0.43). Median OS was 18.2 months in experimental arm and was 12.6 months in control arm (HR 0.71; 95% CI 0.32-1.53; P=0.38). The occurrence of grade 3 or higher neutropenia (69.2% vs. 93.4%, P=0.02) and febrile neutropenia (3.8% vs. 23.3%, P=0.04) was significantly more common in control arm. There was no treatment-related death.
Conclusion:
ERCC1 and RRM1 expression-based chemotherapy did not improve clinical outcomes in advanced NSCLC (NCT01648517).
