Ju-Kyung Lee

Prognostic impact of fibroblast growth factor receptor 2 gene amplification in patients receiving fluoropyrimidine and platinum chemotherapy for metastatic and locally advanced unresectable gastric cancers

Although Fibroblast growth factor receptor (FGFR) 2 gene amplification and its prognostic significance have been reported in resectable gastric cancers, information on these features remains limited in the metastatic setting. The presence of FGFR2 amplification was assessed in formalin-fixed, paraffin-embedded tissues using a quantitative PCR-based gene copy number assay with advanced gastric cancer cohorts. A total of 327 patients with tumor portion of ≥70% were analyzed for clinical features. Among these patients, 260 who received first-line fluoropyrimidine and platinum chemotherapy were analyzed for survival. Sixteen of 327 patients (4.9%) exhibited FGFR2 amplification. The amplification group showed associations with age <65 years, Borrmann type 4 disease, poor performance status, poorly differentiated histology, extra-abdominal lymph node metastases, and bone metastases. The median overall survival (OS) and progression-free survival (PFS) were found to be 12.7 and 5.8 months, respectively. In univariate analysis, PFS did not differ between amplification and no amplification groups (hazard ratio [HR]=1.34, 95% confidence interval [CI]: 0.78-2.31, p=0.290), although the OS was significantly shorter in the amplification group (HR=1.92, 95% CI: 1.13-3.26, p=0.015). However, multivariate analysis indicated that FGFR2 amplification was not an independent prognostic factor for OS (HR=1.42, 95% CI: 0.77-2.61, p=0.261). Although FGFR2 amplification is associated with poorer OS, it does not appear to be an independent prognostic predictor in patients with advanced gastric cancer treated with palliative fluoropyrimidine and platinum chemotherapy.

1474PRANDOMIZED PHASE II STUDY OF BELOTECAN OR TOPOTECAN CHEMOTHERAPY AS SECOND-LINE CHEMOTHERAPY AFTER PLATINUM-BASED FIRST-LINE CHEMOTHERAPY FOR SMALL CELL LUNG CANCER

ABSTRACT Aim: Topotecan has been accepted as second-line therapy for small cell lung cancer (SCLC), in addition, belotecan also been reported to have a significant response rate. Based on these results, we designed prospective randomized phase II trial of belotecan as a second-line treatment in patients with SCLC, who experienced disease progression within 6 months after first-line platinum-containing chemotherapy or chemo-radiotherapy. Methods: We randomly assigned patients to belotecan 0.5 mg/m2 (n=61) or topotecan 1.5 mg/m2 (n=55) for 5 days every 21 days, stratified by response to first-line chemotherapy. The primary end point was response rate (RR). The secondary end points were progression-free survival (PFS), overall survival (OS) and safety profiles. Results: From August 2006 to December 2013, a total of 116 patients were enrolled. The median age was 64 years (range, 28-82), and the ratio of males to females was 0.89. In total, 186 cycles of topotecan (median 2, range 1-9) and 180 cycles of belotecan (median 2, range 1-8) were administered. Median follow-up was 5.6 months. RR of belotecan and topotecan was 19.7% (12/61) and 18.2% (10/55), respectively (p=0.92). Median PFS and OS of belotecan and topotecan was 2.1 months (95% CI 1.43-2.72) versus 2.3 months (1.46-3.07) and 11.2 months (10.2-12.1) versus 12.1 months (10.1-14.0), respectively (p=0.167, 0.659). Grade 3/4 hematologic adverse events with belotecan and topotecan were anemia [13.1% versus 14.5% (p=1.000)] thrombocytopenia [3.3% versus 7.3% (p=0.421)], neutropenia [21.3% versus 43.6% (p=0.016)]. Conclusions: Belotecan showed comparable efficacy to that with topotecan and more favorable toxicity profiles for neutropenia. Disclosure: All authors have declared no conflicts of interest.

Establishment and characterization of patient-derived xenograft models of gastrointestinal stromal tumor resistant to standard tyrosine kinase inhibitors

Gastrointestinal stromal tumors (GISTs) with KIT or platelet-derived growth factor receptor alpha (PDGFRa) oncogenic driver gene mutations, respond to tyrosine kinase inhibitors (TKIs) including imatinib, sunitinib, and regorafenib. However, most patients develop TKI resistance; therefore, novel agents are required. We established three TKI-resistant GIST patient-derived xenograft (PDX) models for effective drug development. These were PDX models harboring primary and secondary KIT and additional mutations; KIT exon 11 (p.Y570_L576del), KIT exon 17 (p.D816E), and PTEN (p.T321fs) mutations in GIST-RX1 from a patient who was unresponsive to imatinib, sunitinib, and sorafenib, and KIT exon 11 (p.K550_splice) and KIT exon 14 (p.T670I) mutations in GIST-RX2 and KIT exon 9 (p.502_503insYA) and KIT exon 17 (p.D820E) mutations in GIST-RX4 from patients with imatinib and imatinib/sunitinib resistance, respectively. The histological features and mutation statuses of GIST PDXs were consistent with those of the original patient tumors, and the models showed TKI sensitivity comparable to clinical responses. Imatinib inhibited the KIT pathway in imatinib-sensitive GIST-T1 but not GIST-RX1, RX2, and RX4. These GIST PDX models will be useful for studying TKI resistance mechanisms and evaluating novel targeted agents in GIST.

Abstract A13: Establishment and characterization of patient-derived xenograft models of gastrointestinal stromal tumor resistant to standard tyrosine kinase inhibitors

BACKGROUND: The prognosis of gastrointestinal stromal tumor (GIST) has been dramatically improved after introduction of imatinib which can inhibit the driver mutated oncoproteins,KIT or PDGFRa. However, most patients eventually develop resistance to the tyrosine kinase inhibitors (TKIs) targeting these oncoproteins including imatinib, sunitinib, or regorafenib. The paucity of TKIs-resistant commercially available GIST cell lines hampers development of effective therapy for drug-resistant GIST. Therefore, we established patient-derived xenograft (PDX) models that faithfully recapitulate the genetic and phenotypic features of drug-resistant GIST. METHODS: PDXs have been established in NOD-SCID mice with tumor fragments of patients with metastatic and/or unresectable GIST after failure of at least imatinib and/or sunitinib. The histological and genomic similarities between all xenografts and the parental tumors have been confirmed using HE 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A13.

Abstract B211: Comparison of detection of FGFR2 amplification by quantitative real-time-PCR (qPCR) and fluorescent in situ hybridization (FISH) in gastric cancer.

Background: Fibroblast growth factor receptor 2 (FGFR2) amplification is associated with tumorigenesis of gastric cancer and can be a promising molecular target for the treatment of FGFR2-amplified gastric cancer. So far, the most optimal single method to screen patients with FGFR2 amplification has not been determined. To screen patients with gastric cancer harboring FGFR2 amplification, we aim to investigate whether qPCR can replace the FISH method which is the golden standard but less sensitive and much more expensive than qPCR. Methods: FISH (Abnova, #FG0018) and qPCR (Applied Biosystems, HS05182482_cn) method for FGFR2 amplification were performed with formalin-fixed paraffin-embedded (FFPE) tissues of patients with gastric cancer who were diagnosed from 2007 to 2012 in Asan Medical Center, Seoul, Korea, and whose FFPE tissues contained at least 70% of tumor cells. qPCR was conducted initially in 26 patients who had both endoscopic biopsy and surgical tissues in the diagnosis to figure out which samples are better between biopsy and surgical tissues. According to the results, 182 patients with endoscopic biopsy tissues were further included. FISH was defined as positive in case of FGFR2 to CEP10 ratio > 2.0. Results: In 26 patients who had paired endoscopic biopsy and surgical samples, the qPCR-based copy number assay for FGFR2 amplification was more sensitive in biopsy samples; i.e., FGFR2 copy number by qPCR was higher in biopsy samples in 13 (50%) patients, while it was higher in surgical samples only in 3 (11.5%) patients. In a total of 208 endoscopic biopsy FFPE samples including 182 patients with biopsy tissues, copy number of FGFR2 ranged from 0.8 to 399.0 (median 15.9) by qPCR and from 0.7 to 166.9 (median 6.1) by FISH. 16 biopsy samples showing FGFR2 copy number > 10 by qPCR were all FISH-positive, while 192 biopsy samples showing FGFR2 copy number 10 in biopsy tissues by qPCR, the copy numbers were very well correlated between qPCR and FISH in all patients, and were also over 10 in surgical tissues regardless of methods in 26 patients. The positive rate of FGFR2 amplification was 7.7% with a cut-off value of 10 by qPCR. Conclusion: This study suggests that it is better to use biopsy samples than surgical tissues to detect FGFR2 amplification by qPCR; and for patient screening in gastric cancer, the optimal cut-off value for definite FGFR2 amplification by qPCR is 10 in comparison with the results of FISH. Clinical relevance of intermediate FGFR2 copy number elevation < 10 by qPCR needs to be addressed in future clinical trials using FGFR2 inhibitors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B211. Citation Format: Young-Soon Na, Young Soo Park, Min-Hee Ryu, Chae-Won Lee, Hye Jin Park, Ju-Kyung Lee, Sook Ryun Park, Baek-Yeol Ryoo, Yoon-Koo Kang. Comparison of detection of FGFR2 amplification by quantitative real-time-PCR (qPCR) and fluorescent in situ hybridization (FISH) in gastric cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B211.