Su Jin Heo

Cumulative Metformin Use and Its Impact on Survival in Gastric Cancer Patients After Gastrectomy.

OBJECTIVEnThe aim of this study was to evaluate the association between metformin and survival of gastric cancer (GC) patients.nnnBACKGROUNDnMetformin has recently received attention as a potential anticancer treatment. However, no study has shown the survival benefit of metformin for GC patients.nnnMETHODSnA total of 1974 GC patients who underwent curative gastrectomy were compared for survival according to groups; 132 diabetic patients treated with metformin, 194 diabetic patients without metformin, and 1648 non-diabetic patients.nnnRESULTSnDuring the median follow-up period of 6.2 years (interquartile range, 4.7-7.8 years), 381 patients (19.3%) died, including 302 (15.3%) who died from GC. The non-diabetic patients had significantly better recurrence-free survival (RFS; P < 0.0001), cancer-specific survival (CSS; P = 0.006), and overall survival (OS; P < 0.0001). However, the diabetic patients treated with metformin had a significantly better prognosis than those who were not (OS: hazard ratio [HR] = 0.584, 95% confidence interval [CI], 0.369-0.926; CSS: HR = 0.57, 95% CI, 0.334-0.975; RFS: HR = 0.633, 95% CI, 0.410-0.977), and metformin treatment prolonged survival in diabetic patients to a rate comparable to that in non-diabetic patients. In multivariable analysis using the Cox proportional hazard model with time-dependent covariates, each cumulative 6 months of metformin use was significantly associated with a decreased risk of recurrence, cancer-specific mortality, and all-cause mortality (RFS: HR = 0.864, 95% CI, 0.797-0.937; CSS: HR = 0.865, 95% CI, 0.782-0.958; OS: HR 0.870, 95% CI, 0.801-0.945).nnnCONCLUSIONSnThe increased cumulative duration of metformin use decreased the recurrence, all-cause mortality, and cancer-specific mortality rates among GC patients with diabetes who underwent gastrectomy.

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.

Prediction of short- and long-term survival for advanced cancer patients after ICU admission

BackgroundIntensive care unit (ICU) admission of advanced cancer patients is controversial because it is associated with poor short-term prognosis. However, ICU admission of these patients might also result in administration of specific anticancer treatments and evaluation of tumor characteristics, which could influence long-term outcomes. Herein, we investigate whether there is a relationship between ICU admission and long-term outcomes for advanced cancer patients.MethodsWe analyzed 116 advanced cancer patients who were admitted to the ICU at Severance Hospital, Yonsei University, between January 2010 and December 2012. We excluded palliative care-only patients. We analyzed demographic, clinical, and survival data of patients admitted to the ICU, and we identified patient characteristics that were measured upon presentation to ICU to determine whether any of these are prognostic or predictive factors of short- or long-term survival.ResultsThe median age of our study sample was 64xa0years. Sixty-nine (59.5xa0%) patients were male. Lung, breast, and stomach were the most common primary tumor sites. Eighty-seven (75xa0%) patients had received active anticancer treatment within the past 30xa0days. The main cause of ICU admission was acute respiratory failure (73xa0%); thus, 102 (87.9xa0%) patients were managed with conventional mechanical ventilation, 99 (85.3xa0%) patients in vasopressor and 31 (26.7xa0%) patients received continuous renal replacement therapy (CRRT). Twenty-four (20.7xa0%) patients were in postresuscitation status before ICU admission. The ICU, hospital, and 6-month survival rates were 51.7, 31.0, and 15.5xa0%, respectively. APACHE II score (HR 2.86, 95xa0% CI 1.00–8.15, Pu2009<u20090.050) and need for CRRT (HR 2.14, 95xa0% CI 1.24–3.70, Pu2009<u20090.007) were associated with ICU mortality in a Cox-regression model. Eastern Cooperative Oncology Group (ECOG) performance status (HR 1.64, 95xa0% CI 1.03–2.62, Pu2009<u20090.010) was associated with poor prognosis, and controlled disease status (HR 0.372, 95xa0% CI 0.21–0.67, Pu2009<u20090.001) was found to be a good prognostic factor for 6-month survival after ICU admission.ConclusionsClinical factors associated with acute, critical status upon ICU admission, such as APACHE II score and need of CRRT, were associated with a higher risk of ICU mortality and short-term mortality than factors directly associated with the patient’s cancer. To understand the relationship between ICU admission and long-term survival, however, we have to apply more comprehensive approach that also considers tumor characteristics and disease control status.

Preoperative Serum Carcinoembryonic Antigen Level as a Prognostic Factor for Recurrence and Survival After Curative Resection Followed by Adjuvant Chemotherapy in Stage III Colon Cancer.

Background Carcinoembryonic antigen (CEA) is the most widely used tumor marker in colon cancer; however, there has been controversy regarding the significance of preoperative serum CEA level as a prognostic factor for recurrence. In this study, we evaluated the optimal cutoff value and prognostic significance of preoperative serum CEA level in stage III colon cancer.MethodsBased on a retrospective cohort of 965 patients with stage III colon cancer who underwent elective curative surgery and adjuvant chemotherapy with fluoropyrimidine and oxaliplatin (training set), we determined the optimal cutoff value of CEA for recurrence using the Contal and O’Quigley method. We assessed the prognostic value of this cutoff value in terms of disease-free survival (DFS) and overall survival (OS) in a prospective cohort of 268 patients with stage III colon cancer (validation set). A Cox proportional hazards model was used to explore the association of prognostic variables with DFS and OS.ResultsThe statistically determined best cutoff value for CEA was 3xa0ng/mL in the training set. A high CEA level (≥3xa0ng/mL) was associated with inferior DFS (hazard ratio [HR] 4.609, 95xa0% confidence interval [CI] 2.028–10.474) and OS (HR 3.956, 95xa0% CI 1.127–13.882) in the validation set, while multivariate analysis showed that a high CEA level was an independent risk factor for DFS and OS in both study subsets.ConclusionPreoperative serum CEA level is an independent prognostic factor for DFS and OS in patients with stage III colon cancer after curative resection and adjuvant chemotherapy.

A randomized phase II trial of ERCC1 and RRM1 mRNA expression-based chemotherapy versus docetaxel/carboplatin in advanced non-small cell lung cancer.

Objectives To evaluate whether the selection of first-line chemotherapy based on ERCC1 and RRM1 mRNA expression levels would improve clinical outcomes in advanced non-small cell lung cancer (NSCLC) patients.Materials and methodsEligible patients were randomly assigned 1:1 to the experimental and control arms; the experimental arm received gemcitabine/carboplatin (GC) if ERCC1 and RRM1 expression was 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 DC.ResultsThis study was prematurely terminated after the futility analysis of 43 progression-free survival (PFS) events. A total of 55 patients (nxa0=xa026 in the experimental arm, nxa0=xa029 in the control arm) were evaluable for efficacy and toxicity. Nineteen (73.1xa0%) patients were assigned to receive GC, 0 (0.0xa0%) to GV, 4 (15.4xa0%) to DC, and 3 (11.5xa0%) to DV in the experimental arm. The overall response rates were 42.3 and 48.3xa0% in the experimental and control arms, respectively, which were not statistically different (Pxa0=xa00.657). The median PFS was 5.2xa0months in the experimental arm and 5.4xa0months in the control arm (Pxa0=xa00.286). The median overall survival was 17.4xa0months in the experimental arm and 12.6xa0months in the control arm (Pxa0=xa00.638). The occurrence of grade 3 or higher neutropenia (69.2 vs. 93.1xa0%, Pxa0=xa00.035) and febrile neutropenia (3.8 vs. 24.1xa0%, Pxa0=xa00.054) was more common in the control arm.ConclusionERCC1 and RRM1 mRNA expression-based chemotherapy did not improve clinical outcomes in advanced NSCLC (NCT01648517).

A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma

Osteosarcoma is the most common primary bone cancer. It can be cured by aggressive surgery and chemotherapy, but outcomes for metastatic or chemoresistant disease remain dismal. Cancer sequencing studies have shown that the p53 pathway is dysregulated in nearly every case, often by translocation; however, no studies of osteosarcoma evolution or intratumor heterogeneity have been done to date. We studied a patient with chemoresistant, metastatic disease over the course of 3 years. We performed exome sequencing on germline DNA and DNA collected from tumor at three separate time points. We compared variant calls and variant allele frequencies between different samples. We identified subclonal mutations in several different genes in the primary tumor sample and found that one particular subclone dominated subsequent tumor samples at relapse. This clone was marked by a novel TP53-KPNA3 translocation and loss of the opposite-strand wild-type TP53 allele. Future research must focus on the functional significance of such clones and strategies to eliminate them.

Cardiotoxicity of trastuzumab in patients with HER2-positive gastric cancer

Trastuzumab-induced cardiotoxicity (TIC) is the primary adverse event that limits the use of trastuzumab in HER2-positive breast cancer patients. However, the incidence and risk factors of TIC in HER2-positive gastric cancer are not known. Therefore, we evaluated the incidence and predictive factors of TIC in gastric cancer patients treated with trastuzumab in clinical practice. We reviewed cardiac dysfunction in HER2-positive gastric cancer patients between December 2005 and April 2015 in a prospectively-collected database that included prospective clinical trials at Yonsei Cancer Center, Republic of Korea. TIC was defined as an absolute decline in left ventricular ejection fraction (LVEF) of at least 10 percentage points from the baseline to a value less than 55%, as identified by a multiple-gated acquisition scan or an echocardiogram. Among the 115 patients, 70 patients (60.9%) received trastuzumab combined with chemotherapy, and 45 patients (39.1%) received chemotherapy alone as a first-line therapy. Symptomatic heart failure was not observed in either group, but a significant asymptomatic drop in LVEF was noted in five (7.1%) of the trastuzumab combined-group patients and in one (2.2%) chemotherapy-only group patient [hazard ratio (HR), 3.47; 95% confidence interval (CI), 0.40–29.8; P=0.257]. TIC was observed more frequently in elderly patients than in younger patients (HR, per age in year, 1.16; 95% CI, 1.02–1.31; P=0.019). Similar to prior observations in breast cancer, TIC in gastric cancer patients is not frequent or reversible. However, the asymptomatic drop in LVEF should be monitored continually in HER2-positive gastric cancer patients treated with trastuzumab, especially in elderly patients.Trastuzumab-induced cardiotoxicity (TIC) is the primary adverse event that limits the use of trastuzumab in HER2-positive breast cancer patients. However, the incidence and risk factors of TIC in HER2-positive gastric cancer are not known. Therefore, we evaluated the incidence and predictive factors of TIC in gastric cancer patients treated with trastuzumab in clinical practice. We reviewed cardiac dysfunction in HER2-positive gastric cancer patients between December 2005 and April 2015 in a prospectively-collected database that included prospective clinical trials at Yonsei Cancer Center, Republic of Korea. TIC was defined as an absolute decline in left ventricular ejection fraction (LVEF) of at least 10 percentage points from the baseline to a value less than 55%, as identified by a multiple-gated acquisition scan or an echocardiogram. Among the 115 patients, 70 patients (60.9%) received trastuzumab combined with chemotherapy, and 45 patients (39.1%) received chemotherapy alone as a first-line therapy. Symptomatic heart failure was not observed in either group, but a significant asymptomatic drop in LVEF was noted in five (7.1%) of the trastuzumab combined-group patients and in one (2.2%) chemotherapy-only group patient [hazard ratio (HR), 3.47; 95% confidence interval (CI), 0.40-29.8; P=0.257]. TIC was observed more frequently in elderly patients than in younger patients (HR, per age in year, 1.16; 95% CI, 1.02-1.31; P=0.019). Similar to prior observations in breast cancer, TIC in gastric cancer patients is not frequent or reversible. However, the asymptomatic drop in LVEF should be monitored continually in HER2-positive gastric cancer patients treated with trastuzumab, especially in elderly patients.

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.

Depth of response is a significant predictor for long-term outcome in advanced gastric cancer patients treated with trastuzumab

Purpose We aimed to determine and compare the predictive values of depth of response (DpR) and early tumor shrinkage (ETS) on long-term outcomes in gastric cancer patients treated with trastuzumab. Results From a total of 368 computed tomography examinations, DpR and ETS were evaluated. DpR was a significant tumor-size metric in predicting PFS and OS, and showed better discriminatory ability (higher Cτ indices, 0.6957 for PFS; 0.7191 for OS) than ETS. DpR ≥ 45% (vs. < 45%) was the optimal cutoff value, as it was best able to identify patients with longer PFS (median 9.0 vs. 6.3 months, hazard ratio [HR] = 0.608; 95% confidence interval [CI]: 0.335 to 1.104; P = 0.102) and OS (median 23.5 vs. 13.1 months, HR = 0.441; 95% CI: 0.203 to 0.955; P = 0.038). Materials and Methods Sixty-one gastric cancer patients who received first-line trastuzumab-based chemotherapy were assessed for DpR and ETS. We employed Kaplan-Meier estimates, log-rank tests, Cox proportional hazards regression models, time-dependent receiver operating characteristics, and Youdens J index to evaluate and determine cutoff values of DpR and ETS as predictors of progression-free survival (PFS) and overall survival (OS). Conclusions DpR and ETS were significant predictors of long-term outcomes in gastric cancer patients treated with first-line trastuzumab. Validation in prospective trials with larger patient populations is needed.

PTEN loss and level of HER2 amplification is associated with trastuzumab resistance and prognosis in HER2-positive gastric cancer

Background Trastuzumab is an active agent against human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). This study aimed to characterize resistance to trastuzumab-based front-line chemotherapy in HER2+ GC patients and to establish factors predictive of this resistance. Results Among 129 HER2+ GC patients, 25% displayed rapid disease progression within 4 months from initiation of therapy. These patients showed a higher rate of signet ring cell histology, bone metastasis, poor performance status, frequent loss of PTEN expression, and low HER2 amplification index compared with patients who were progression-free for at least 4 months. In contrast, there was no significant difference in the frequency of the PIK3R1 variant. Multivariate analyses confirmed two independent molecular predictors for trastuzumab resistance: loss of PTEN expression and low HER2 amplification index (<5). Patients with one or both molecular predictors at diagnosis exhibited worse progression-free and overall survival compared to those without risk factors (p < 0.001 and p = 0.001, respectively). Conclusion In HER2+ GC patients, loss of PTEN expression and low HER2 AI correlated with resistance to trastuzumab-based therapy and dismal prognosis. Since patients harboring these molecular predictors are unlikely to respond to trastuzumab-based therapy, other novel therapeutic targets needed to be considered. Methods HER2+ GC patients who were treated with trastuzumab in combination with either 5-fluorouracil/cisplatin or capecitabine/cisplatin were enrolled. Clinicopathologic features and molecular alterations of HER2, phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1), and phosphatase and tensin homolog (PTEN) were correlated with treatment outcome. Factors predictive of resistance were also explored.