Jee Hung Kim

Effects of microsatellite instability on recurrence patterns and outcomes in colorectal cancers

Background:Among colorectal cancers (CRCs), high-frequency microsatellite instability (MSI-H) is associated with a better prognosis, compared with low-frequency MSI or microsatellite stability (MSI-L/MSS). However, it is unclear whether MSI affects the prognosis of recurrent CRCs.Methods:This study included 2940 patients with stage I–III CRC who underwent complete resection. The associations of MSI status with recurrence patterns, disease-free survival (DFS), overall survival from diagnosis to death (OS1), and overall survival from recurrence to death (OS2) were analysed.Results:A total of 261 patients (8.9%) had MSI-H CRC. Patients with MSI-H CRC had better DFS, compared to patients with MSI-L/MSS CRC (hazard ratio (HR): 0.619, P<0.001). High-frequency microsatellite instability CRC was associated with more frequent local recurrence (30.0% vs 12.0%, P=0.032) or peritoneal metastasis (40.0% vs 12.3%, P=0.003), and less frequent lung (10.0% vs 42.5%, P=0.004) or liver metastases (15.0% vs 44.7%, P=0.01). Recurrent MSI-H CRC was associated with worse OS1 (HR: 1.363, P=0.035) and OS2 (HR: 2.667, P<0.001). An analysis of patients with colon cancer yielded similar results.Conclusions:Recurrence patterns differed between MSI-H CRC and MSI-L/MSS CRC, and recurrent MSI-H CRCs had a worse prognosis.

Detection of activating and acquired resistant mutation in plasma from EGFR-mutated NSCLC patients by peptide nucleic acid (PNA) clamping-assisted fluorescence melting curve analysis

This study was designed to prospectively examine whether peptide nucleic acid clamping-assisted fluorescence melting curve analysis (PANAMutyper™) is feasible for the detection of activating and acquired resistant epidermal growth factor receptor (EGFR) mutation in plasma. Patients with non-small cell lung cancer harboring activating EGFR mutations who were scheduled to undergo EGFR-tyrosine kinase inhibitors (EGFR-TKIs) were enrolled between September 2011 and March 2015. A total of 102 patients with EGFR-mutated lung cancer were enrolled, 53 had available plasma samples at disease progression, and 28 underwent serial plasma sampling during EGFR-TKI treatment. EGFR-TKI-sensitizing and T790M mutations were detected in the plasma of 68.6% (70/102) at baseline and 30.2% (16/53) at disease progression, respectively. The concordance rates for matched tissue and plasma samples were 80.4% and 90.2% for E19del and L858R mutations at baseline and 56.3% for T790M mutation at disease progression. The sustained presence of plasma EGFR mutations four weeks after EGFR-TKI predicted a poor objective response rate (30.0% vs. 87.5%, P = 0.025), as well as worse progression-free survival (hazard ratio [HR], 4.381) and overall survival (HR, 5.475). Longitudinal analysis could detect T790M mutations earlier than disease progression based on imaging study (median time from appearance of T790M in plasma samples to progression at imaging scan, 103 days). In conclusion, PANAMutyper™ is reliable for detecting activating and acquired resistant EGFR mutation in plasma, and predicts responses to EGFR-TKI via longitudinal monitoring of EGFR mutation during treatment.This study was designed to prospectively examine whether peptide nucleic acid clamping-assisted fluorescence melting curve analysis (PANAMutyper™) is feasible for the detection of activating and acquired resistant epidermal growth factor receptor (EGFR) mutation in plasma. Patients with non-small cell lung cancer harboring activating EGFR mutations who were scheduled to undergo EGFR-tyrosine kinase inhibitors (EGFR-TKIs) were enrolled between September 2011 and March 2015. A total of 102 patients with EGFR-mutated lung cancer were enrolled, 53 had available plasma samples at disease progression, and 28 underwent serial plasma sampling during EGFR-TKI treatment. EGFR-TKI-sensitizing and T790M mutations were detected in the plasma of 68.6% (70/102) at baseline and 30.2% (16/53) at disease progression, respectively. The concordance rates for matched tissue and plasma samples were 80.4% and 90.2% for E19del and L858R mutations at baseline and 56.3% for T790M mutation at disease progression. The sustained presence of plasma EGFR mutations four weeks after EGFR-TKI predicted a poor objective response rate (30.0% vs. 87.5%, P = 0.025), as well as worse progression-free survival (hazard ratio [HR], 4.381) and overall survival (HR, 5.475). Longitudinal analysis could detect T790M mutations earlier than disease progression based on imaging study (median time from appearance of T790M in plasma samples to progression at imaging scan, 103 days). In conclusion, PANAMutyper™ is reliable for detecting activating and acquired resistant EGFR mutation in plasma, and predicts responses to EGFR-TKI via longitudinal monitoring of EGFR mutation during treatment.

Role of adjuvant chemotherapy in locally advanced rectal cancer with ypT0-3N0 after preoperative chemoradiation therapy and surgery

BackgroundWe aimed to explore the clinical benefit of adjuvant chemotherapy (AC) with fluoropyrimidine in patients with ypT0-3N0 rectal cancer after preoperative chemoradiation therapy (CRT) followed by total mesorectal excision (TME).MethodsPatients with ypT0-3N0 rectal cancer after preoperative CRT and TME were included using prospectively collected tumor registry cohort between January 2001 and December 2013. Patients were categorized into two groups according to the receipt of AC. Disease-free survival (DFS) and overall survival (OS) were compared between the adjuvant and observation groups. To control for potential confounding factors, we also calculated propensity scores and performed propensity score-matched analysis for DFS and OS.ResultsOf the 339 evaluated patients, 87 patients (25.7%) did not receive AC. There were no differences in DFS (hazard ratio [HR], 0.921; 95% confidence interval [CI], 0.562–1.507; P = 0.742) and OS (HR, 0.835; 95% CI, 0.423–1.648; P = 0.603) between the adjuvant and observation groups. After propensity score matching, DFS (HR, 1.129; 95% CI, 0.626–2.035; P = 0.688) and OS (HR, 1.200; 95% CI, 0.539–2.669; P = 0.655) did not differ between the adjuvant and observation groups. Advanced T stage and positive resection margin were independently associated with inferior DFS and OS on multivariate analysis.ConclusionsAC did not improve DFS and OS for patients with ypT0-3N0 rectal cancer after preoperative CRT followed by TME in this cohort study. The confirmative role of AC in locally advanced rectal cancer should be evaluated in prospective randomized trials with a larger sample size.

Abstract 430: Novel biomarkers for VEGFR inhibitors in metastatic renal cell carcinoma: BIM expression, and germline polymorphisms of BIM and PIK3R1

Molecular targeted therapy, especially VEGFR tyrosine-kinase inhibitors (TKIs) including sunitinib, pazopanib and sorafenib has been the most efficacious therapy for metastatic renal cell carcinoma (mRCC). However, approximately 35% of mRCC patients do not get the benefit from TKIs treatment, due to resistance and/or drug induced toxicities. Pro-apoptotic Bcl-2 family member (BIM) is a particularly critical mediator of targeted therapy-induced apoptosis in solid tumors. In previous, it had known that TKIs induced to BIM upregulation and then accelerated to apoptosis of tumor. However, according to recent several studies, BIM germline deletion polymorphism was identified as one of the primary resistant mechanisms of various TKIs in EGFR mutated NSCLC or CML. In addition, the alteration of phosphoinositide 3 kinase(PIK3)/protein kinase B(AKT) pathway has also been found as important mechanism in various cancer cell growth, proliferation and survival. PI3KR1 encodes the p85α subunit, regulatory subunits of Class IA PIK3s. Germline PIK3R1 variant M326I(c.978G>A) might affect the sensitivity of receptor tyrosine kinase (RTK) inhibitors and its downstream pathway inhibitors. We evaluated the possibility of BIM, PIK3R1 as a potential biomarker for VEGFR TKIs in mRCC. BIM deletion polymorphism status of gDNA from formalin fixed paraffin embedded (FFPE) tumor tissues and peripheral blood mononucleated cells (PBMC) of mRCC patients was determined by separated PCR. And we evaluated BIM protein expression by immunohistochemistry. We also evaluated PIK3R1 germline mutation by pyrosequencing in PBMC of mRCC patients.Germline BIM deletion accounted for 17.8% of total 124 mRCC patients. Unlike with previous other studies, our data suggested that BIM wild type showed tendency to poor prognosis with sunitinib or sorafenib treatments for clear cell type RCC (median OS of BIM wild and deleted type: 44.9 vs 67.3 months, p = 0.279), and high expression of BIM (median OS of BIM low( 50%) respectively: 76.5 vs 60.0 vs 21.3 months, p = 0.005). In addition, we found 26% (19/71) of the germline PIK3R1 variant in mRCC. Patients with PIK3R1 germline variant showed a tendency of poor prognosis to 1st line VEGFR TKI treatment than wild type (median PFS: 7.78 vs 15.87months, p = 0.342). Especially PFS of 1st line sunitinib treatment was significantly shorter in PIK3R1 variant compared to wild type (median PFS 7.78 vs 16.33 months, p = 0.004). But, there is no difference in mTOR inhibitor sensitivity both with PIK3R1 or BIM polymorphism.In conclusion, BIM expression and germline variants of BIM and PIK3R1 might be candidate biomarkers for VEGFR TKIs in mRCC. Citation Format: Jee Hung Kim, Woo Sun Kwon, Won Suk Lee, Tae Soo Kim, Kyu Hyun Park, Jae Kyung Roh, Joong Bae Ahn, Hyun Cheol Chung, Sun Young Rha. Novel biomarkers for VEGFR inhibitors in metastatic renal cell carcinoma: BIM expression, and germline polymorphisms of BIM and PIK3R1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 430.

Differences in the Efficacies of Pazopanib and Gemcitabine/Docetaxel as Second-Line Treatments for Metastatic Soft Tissue Sarcoma

Background: We retrospectively investigated the treatment outcomes of second-line treatment with pazopanib or gemcitabine/docetaxel in patients with advanced soft tissue sarcoma (STS). Methods: Ninety-one patients who were treated with pazopanib or gemcitabine/docetaxel for advanced STS between 1995 and 2015 were analyzed. Results: Forty-six and 45 patients received pazopanib and gemcitabine/docetaxel, respectively. The median progression-free survival for the group treated with pazopanib was 4.5 months compared with 3.0 months for the gemcitabine/docetaxel group (p = 0.593). The median overall survival for the group treated with pazopanib was 12.6 months compared with 14.2 months for the gemcitabine/docetaxel group (p = 0.362). The overall response rates (ORRs) were 6.5 and 26.7% in the pazopanib and gemcitabine/docetaxel groups, respectively. The following parameters had ORRs favoring gemcitabine/docetaxel: age ≥50 years (31.6 vs. 2.9%, p = 0.006), histologic grade 1–2 (40.9 vs. 0%, p = 0.001), and poor first-line treatment response (23.3 vs. 3.0%, p = 0.022). Gemcitabine/docetaxel was associated with better ORRs for the following histologic subtypes: leiomyosarcoma (p = 0.624), malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma (p = 0.055), and angiosarcoma (p = 0.182). However, the ORR of synovial sarcoma favored pazopanib (p = 0.99). Conclusions: The efficacies of pazopanib and gemcitabine/docetaxel as second-line treatments after doxorubicin or ifosfamide failure differed among clinical and histologic subgroups and appeared to facilitate a more personalized treatment approach for advanced STS.

Marked Loss of Muscle, Visceral Fat, or Subcutaneous Fat After Gastrectomy Predicts Poor Survival in Advanced Gastric Cancer: Single-Center Study from the CLASSIC Trial

BackgroundThere is increasing interest in the influence of body composition on oncological outcomes. We evaluated the role of skeletal muscle and fat among patients with gastric cancer (GC) who underwent gastrectomy with or without adjuvant chemotherapy, as well as those changes’ associations with survival outcomes.MethodsThe present study evaluated 136 patients with GC who were enrolled in the CLASSIC Trial at Yonsei Cancer Center. Baseline body compositions including skeletal muscle area, Hounsfield units (HU), visceral fat area, and subcutaneous fat area were measured by preoperative computed tomography (CT). CT before and after the gastrectomy were used to determine the 6-month relative changes in body composition parameters. Continuous variables were dichotomized according to the best cutoff values by Contal and O’Quigley method.ResultsSeventy-three patients (53.7%) underwent surgery alone, and 63 patients (46.3%) underwent surgery followed by adjuvant chemotherapy. The baseline body composition parameters were not associated with disease-free survival (DFS) or overall survival (OS). Except for the HU, the marked loss of muscle, visceral fat, or subcutaneous fat significantly predicted shorter DFS and OS. Patients with a marked loss in at least one significant body composition parameter had significantly shorter DFS (hazard ratio 2.9, 95% confidence interval 1.7–4.8, P < 0.001) and OS (hazard ratio 2.9, 95% confidence interval 1.7–5.0, P < 0.001).ConclusionsMarked loss in body composition parameters significantly predicted shorter DFS and OS among patients with GC who underwent gastrectomy. Postoperative nutrition and active healthcare interventions could improve the prognosis of these GC patients.

Prognoses and Clinical Outcomes of Primary and Recurrent Uveal Melanoma

Purpose Uveal melanoma has a very poor prognosis despite successful local primary tumor treatment. In this study, we investigated prognostic factors that more accurately reflected the likelihood of recurrence and survival and delineated a prognostic model that could effectively identify different risk groups based on initial clinical parameters. Materials and Methods Prognostic factors associated with distant recurrence, recurrence-free survival (RFS), progression-free survival, and overall survival from distant recurrence to death (OS2) were analyzed in 226 patients with stage I-III uveal melanoma who underwent primary local therapy. Results Forty-nine patients (21.7%) had distant recurrences, which occurred most frequently in the liver (87.7%). In a multivariate analysis, local radiotherapy improved RFS among patients with multiple recurrence risk factors relative to excision (not reached vs. 19.0 months, p=0.004). Patients with BRCA1-associated protein-1 (BAP1)‒negative primary tumors showed a longer RFS duration after primary treatments, while those with BAP1-negative metastatic tissues had a shorter OS2 compared to those with BAP1-positive tumors, both not statistically insignificance (RFS: not reached vs. 82.0 months, p=0.258; OS2: 15.7 vs. 24.4 months, p=0.216). Male sex (hazard ratio [HR], 3.79; p=0.012), a short RFS (HR, 4.89; p=0.014), and a largest metastatic tumor linear diameter ≥ 45 mm (HR, 5.48; p=0.017) were found to correlate with worse post-recurrence survival. Conclusion Risk factors could be used to classify uveal melanoma cases and subsequently direct individual treatment strategies. Furthermore, metastasectomy appears to contribute to improved survival outcomes.

Assessment of Adrenal Function and Health-Related Quality of Life in Advanced Gastric Cancer Patients Who Received First-Line Chemotherapy

Objective: We performed this prospective study to identify both the incidence of adrenal insufficiency (AI) and health-related quality of life (HRQOL) in advanced gastric cancer (AGC) patients who were treated with the S-1 plus cisplatin (SP) regimen as a first-line palliative chemotherapy. Methods: We assessed adverse events (AEs) observed in 52 patients who received the SP regimen for AGC between January 2009 and June 2010 using the Common Toxicity Criteria Adverse Events (CTCAE) version 3.0. Adrenal function was assessed at baseline and 12 weeks after chemotherapy using the low-dose adrenocorticotropic hormone stimulation test. HRQOL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0 (EORTC-QLQ C30). Results: The incidence of AI was 30.8% (n = 16) and of AE observed 55% (n = 29) among 52 patients after 12 weeks of chemotherapy. Of 29 patients with AE, 34.4% (n = 10) were diagnosed with AI, and of 23 patients without AE, 26.1% (n = 6) were diagnosed with AI. Conclusion: The incidence of secondary AI in AGC patients was not rare and was not correlated with the presence of nonspecific AEs. Although patients diagnosed with AI did not show any related symptoms, they are at risk of potentially life-threatening consequences. Thus, the evaluation of AI could be suggested for patients who received chemotherapy.

Abstract 808: Microsatellite instability in metastatic colorectal cancer (mCRC)

Background: Although early stage colorectal cancer (CRC) with microsatellite instability (MSI) phenotype has a more favorable prognosis, impact on outcome of MSI status in metastatic CRC (mCRC) is rarely known. We aim to explore patterns of metastatic spread and prognosis of CRC with MSI-H (high-level MSI) in comparison to MSI-L (low-level of MSI)/MSS. Methods: Patients with mCRC who underwent testing for MSI were identified using retrospective cohort of Yonsei Cancer Center. Patients were categorized to MSI status (MSI-H vs. MSS-L/MSS). Patterns of metastatic spread, surgical resection after recurrence and outcome between two groups were compared. Results: A total of 944 patients were evaluated. Of all, 34 patients (3.6%) had MSI-H tumors. A distinct pattenrs of metastatic spread was observed in MSI-H tumors, namely higher rates of peritoneal metastasis (41% vs 10%, P Conclusions: Different patterns of metastatic spread and receipt of surgical resection in MSI-H mCRC is demonstrated in this study. In addition, MSI-H phenotype is associated with poorer survival in mCRC on the contrary to early stage disease. Future studies focusing on deeper understanding of tumor biology and therapeutic response in this rare disease entity are warranted. Citation Format: Jee Hung KIM, Chang-gon Kim, Joong Bae Ahn, MinKyu Jung, Seung Hoon Beom, Joo Hoon Kim, Soo Jin Heo, Sang Joon Shin. Microsatellite instability in metastatic colorectal cancer (mCRC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 808.