Publications by authors named "Sae-Won Han"

213 Publications

Sotorasib for previously treated colorectal cancers with KRAS mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial.

Lancet Oncol 2022 Jan 15;23(1):115-124. Epub 2021 Dec 15.

Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA, Australia.

Background: Sotorasib, a specific, irreversible KRAS protein inhibitor, has shown monotherapy clinical activity in KRAS-mutated solid tumours, including colorectal cancer, in the CodeBreaK100 phase 1 trial. We aimed to investigate the activity and safety of sotorasib in phase 2 of the trial.

Methods: In this single-arm, phase 2 trial, adult patients with KRAS-mutated advanced solid tumours were enrolled, from 59 medical centres in 11 countries, if they were aged 18 years or older, had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Only data for patients with colorectal cancer, enrolled at 33 medical centres in nine countries, are presented from this basket trial. To be enrolled, the patients had to have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment. These patients were administered 960 mg sotorasib orally once per day until disease progression, development of unacceptable side-effects, withdrawal of consent, or death. The primary endpoint was objective response (complete or partial response) as assessed by blinded independent central review. Response was evaluated in patients who received at least one dose of sotorasib and had at least one measurable lesion at baseline; safety was evaluated in patients who received at least one dose of sotorasib. This analysis is a prespecified analysis triggered by the phase 2 colorectal cancer cohort. This study is registered with ClinicalTrials.gov, NCT03600883, and is active but no longer recruiting.

Findings: On March 1, 2021, at data cutoff, 62 patients with KRAS-mutant colorectal cancer had been enrolled between Aug 14, 2019, and May 21, 2020, and had received at least one dose of sotorasib monotherapy. Objective response was observed in six (9·7%, 95% CI 3·6-19·9) of 62 patients, all with partial response. Treatment-related adverse events at grade 3 occurred in six (10%) patients, the most common of which was diarrhoea (two [3%] of 62 patients), and at grade 4 occurred in one (2%) patient (blood creatine phosphokinase increase); no fatal events were recorded. Serious treatment-related adverse events occurred in two (3%) patients (back pain and acute kidney injury).

Interpretation: Although the 9·7% overall response rate did not reach the benchmark, oral administration of sotorasib once per day showed modest anti-tumour activity and manageable safety in these heavily pretreated chemorefractory patients. Sotorasib is under evaluation in combination with other therapeutics to increase potential activity and overcome potential resistance mechanisms.

Funding: Amgen.
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http://dx.doi.org/10.1016/S1470-2045(21)00605-7DOI Listing
January 2022

Patient-derived organoids as a preclinical platform for precision medicine in colorectal cancer.

Mol Oncol 2021 Nov 30. Epub 2021 Nov 30.

Department of Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Korea.

Patient-derived organoids are being considered as models that can help guide personalized therapy through in vitro anticancer drug response evaluation. However, attempts to quantify in vitro drug responses in organoids and compare them with responses in matched patients remain inadequate. In this study, we investigated whether drug responses of organoids correlate with clinical responses of matched patients and disease progression of patients. Organoids were established from 54 patients with colorectal cancer who (except for one patient) did not receive any form of therapy before, and tumor organoids were assessed through whole-exome sequencing. For comparisons of in vitro drug responses in matched patients, we developed an 'organoid score' based on the variable anticancer treatment responses observed in organoids. Very interestingly, a higher organoid score was significantly correlated with a lower tumor regression rate after the standard-of-care treatment in matched patients. Additionally, we confirmed that patients with a higher organoid score (≥ 2.5) had poorer progression-free survival compared with those with a lower organoid score (< 2.5). Furthermore, to assess potential drug repurposing using an FDA-approved drug library, ten tumor organoids derived from patients with disease progression were applied to a simulation platform. Taken together, organoids and organoid scores can facilitate the prediction of anticancer therapy efficacy, and they can be used as a simulation model to determine the next therapeutic options through drug screening. Organoids will be an attractive platform to enable the implementation of personalized therapy for colorectal cancer patients.
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http://dx.doi.org/10.1002/1878-0261.13144DOI Listing
November 2021

A Real-world Efficacy of Nab-paclitaxel Monotherapy in Metastatic Breast Cancer.

Cancer Res Treat 2021 Aug 13. Epub 2021 Aug 13.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Purpose: We aimed to assess the real-world efficacy of nab-paclitaxel in metastatic breast cancer patients.

Materials And Methods: This is a retrospective study performed in two tertiary referral hospitals in Korea. Patients with metastatic breast cancer treated with nab-paclitaxel (Abraxane®) between March 2016 and March 2020 were enrolled.

Results: A total of 102 patients with metastatic breast cancer were included. Patients were heavily pre-treated with a median of 4 prior lines of chemotherapy (4.5 lines when including endocrine therapy), and 66 (64.7%) patients were exposed to taxanes in the metastatic setting. According to St. Gallen molecular subtypes, 36 (35.3%) patients were Luminal A, 28 (27.5%) were Luminal B, 18 (17.7%) were HER2-positive, and 20 (19.6%) had triple-negative disease. Fifty (49.0%) patients were treated with a 3-weekly regimen (260 mg/m2 on day 1 every 3 weeks), and 52 (51.0%) were treated with a weekly regimen (100 mg/m2 every week). Objective response rate was 22.9%. After a median follow-up of 22.0 months, median progression-free survival (PFS) was 4.0 months (95% CI, 2.6 to 4.8) and median overall survival was 8.7 months (95% CI, 7.5 to 11.2). Patients treated with weekly regimen had longer PFS compared to 3-weekly regimen (5.5 vs. 2.3 months, p<0.001). Multivariate analysis revealed the treatment regimen as an independent prognostic factor for PFS. There was no grade 3 or 4 hypersensitivity reaction.

Conclusion: This real-world data shows that nab-paclitaxel is a reasonable treatment option in heavily pre-treated and/or taxane-exposed metastatic breast cancer patients.
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http://dx.doi.org/10.4143/crt.2021.394DOI Listing
August 2021

Circulating tumor DNA sequencing in colorectal cancer patients treated with first-line chemotherapy with anti-EGFR.

Sci Rep 2021 08 11;11(1):16333. Epub 2021 Aug 11.

Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Circulating tumor DNA (ctDNA) may reveal dynamic tumor status during therapy. We conducted serial ctDNA analysis to investigate potential association with clinical outcome in metastatic colorectal cancer (mCRC) patients receiving chemotherapy. Tissue KRAS/NRAS wild-type mCRC patients were enrolled and treated with first-line cetuximab-containing chemotherapy. ctDNA isolated from plasma were analyzed by next generation sequencing (NGS) with 16 targeted gene panel. Among 93 patients, 84 (90.3%) had at least 1 somatic mutation in baseline ctDNA samples (average 2.74). Five patients with KRAS or NRAS hotspot mutation in the ctDNA showed significantly worse progression-free survival (PFS) (p = 0.029). Changes in average variant allele frequency (VAF) in ctDNA showed significant correlation with tumor size change at the time of first response evaluation (p = 0.020) and progressive disease (PD) (p = 0.042). Patients whose average VAF decreased below cutoff (< 1%) at the first evaluation showed significantly better PFS (p < 0.001), and the average VAF change further discriminated the PFS in the patients in partial response (p = 0.018). At the time of PD, 54 new mutations including KRAS and MAP2K1 emerged in ctDNA. ctDNA sequencing can provide mutation profile that could better reflect tumor mutation status and predict treatment outcome.
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http://dx.doi.org/10.1038/s41598-021-95345-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358023PMC
August 2021

Impact of UGT1A1 genotype on the efficacy and safety of irinotecan-based chemotherapy in metastatic colorectal cancer.

Cancer Sci 2021 Nov 31;112(11):4669-4678. Epub 2021 Aug 31.

Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea.

The phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second-line treatment for metastatic colorectal cancer. We evaluated the associations between the UGT1A1 genotype linked to adverse events-caused by irinotecan-and the efficacy and safety of mXELIRI and FOLFIRI. The UGT1A1 genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression-free survival, response rate, and safety were assessed. The UGT1A1 genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12-2.09; P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62-1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79-1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39-1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second-line chemotherapy in terms of efficacy and safety regardless of the UGT1A1 genotype.
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http://dx.doi.org/10.1111/cas.15092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586680PMC
November 2021

Tumor microenvironment-adjusted prognostic implications of the KRAS mutation subtype in patients with stage III colorectal cancer treated with adjuvant FOLFOX.

Sci Rep 2021 07 16;11(1):14609. Epub 2021 Jul 16.

Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.

Several studies have reported that the prognostic effect of KRAS mutations on colorectal cancers (CRCs) varies depending on the type of mutation. Considering the effect of KRAS mutations on tumor microenvironment, we analyzed the prognostic significance of KRAS mutation types after adjusting for the tumor-infiltrating lymphocytes (TIL) and tumor-stromal percentage (TSP) statuses. In two independent cohorts, KRAS mutations were analyzed by Sanger sequencing and/or next-generation sequencing. TIL density and the TSP were quantified from whole-slide immunohistochemical images. KRAS-mutant CRCs were divided into three subgroups (G12D/V, other codon 12 mutations and codon 13 mutations) to examine their differential effect on TIL density, the TSP and recurrence-free survival (RFS). Among the KRAS mutations, only the G12D/V subgroups showed significantly less TIL infiltration than the wild-type CRCs. According to survival analysis, G12D/V mutations were associated with short RFS; codon 13 mutations showed discordant trends in the two cohorts, and other codon 12 mutations showed no significant association. Multivariate analysis further supported the prognostic value of G12D/V mutations. This result is not only consistent with a recent study suggesting the immunosuppressive effect of mutant KRAS but also provides insight into the type-specific prognostic effect of KRAS mutations.
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http://dx.doi.org/10.1038/s41598-021-94044-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285533PMC
July 2021

A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer.

Invest New Drugs 2021 10 7;39(5):1335-1347. Epub 2021 Apr 7.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Seoul, Republic of Korea.

Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer. Methods This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used. Results In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively. Conclusion This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted. Trial registration number NCT03076957 (Registered at March 10, 2017).
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http://dx.doi.org/10.1007/s10637-021-01110-9DOI Listing
October 2021

Phase II Trial of Postoperative Adjuvant Gemcitabine and Cisplatin Chemotherapy Followed by Chemoradiotherapy with Gemcitabine in Patients with Resected Pancreatic Cancer.

Cancer Res Treat 2021 Oct 30;53(4):1096-1103. Epub 2020 Dec 30.

Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Despite curative resection, the 5-year survival for patients with resectable pancreatic cancer is less than 20%. Recurrence occurs both locally and at distant sites and effective multimodality adjuvant treatment is needed.

Materials And Methods: Patients with curatively resected stage IB-IIB pancreatic adenocarcinoma were eligible. Treatment consisted of chemotherapy with gemcitabine 1,000 mg/m2 on days 1 and 8 and cisplatin 60 mg/m2 on day 1 every 3 weeks for two cycles, followed by chemoradiotherapy (50.4 Gy/28 fx) with weekly gemcitabine (300 mg/m2/wk), and then gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks for four cycles. The primary endpoint was 1-year disease-free survival rate. The secondary endpoints were disease-free survival, overall survival, and safety.

Results: Seventy-four patients were enrolled. One-year disease-free survival rate was 57.9%. Median disease-free and overall survival were 15.0 months (95% confidence interval [CI], 11.6 to 18.4) and 33.0 months (95% CI, 21.8 to 44.2), respectively. At the median follow-up of 32 months, 57 patients (77.0%) had recurrence including 11 patients whose recurrence was during the adjuvant treatment. Most of the recurrences were systemic (52 patients). Stage at the time of diagnosis (70.0% in IIA, 51.2% in IIB, p=0.006) were significantly related with 1-year disease-free survival rate. Toxicities were generally tolerable, with 53 events of grade 3 or 4 hematologic toxicity and four patients with febrile neutropenia.

Conclusion: Adjuvant gemcitabine and cisplatin chemotherapy followed by chemoradiotherapy with gemcitabine and maintenance gemcitabine showed efficacy and good tolerability in curatively resected pancreatic cancer.
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http://dx.doi.org/10.4143/crt.2020.928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524012PMC
October 2021

Circulating Tumor Marker Isolation with the Chemically Stable and Instantly Degradable (CSID) Hydrogel ImmunoSpheres.

Anal Chem 2021 01 18;93(2):1100-1109. Epub 2020 Dec 18.

Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea.

Here, we present chemically stable and instantly degradable (CSID) hydrogel immunospheres for the isolation of circulating tumor cells (CTCs) and circulating tumor exosomes (CTXs). The CSID hydrogels, which are prepared by the hybridization of alginate and poly(vinyl alcohol), show an equilibrium swelling ratio (ESR) of at pH 7, with a highly stable pH-responsive property. The present hybrid hydrogel is not easily disassociated in the biological buffers, thus being suitable for use in "liquid biopsy", requiring a multistep, long-term incubation process with biological samples. Also, it is gradually degraded by the action of chelating agents; effortless retrieval of the circulating markers has been achieved. Then, we modified the CSID hydrogel spheres with the anti-EpCAM antibody ("C-CSID ImmunoSpheres") and the anti-CD63 antibody ("E-CSID ImmunoSpheres") to isolate two promising circulating markers in liquid biopsy: CTCs and CTXs. The immunospheres' capabilities for marker isolation and retrieval were confirmed by a fluorescence image, where the spheres successfully isolate and effortlessly retrieve the target circulating markers. Lastly, we applied the CSID hydrogel immunospheres to five blood samples from colorectal cancer patients and retrieved average 10.8 ± 5.9 CTCs/mL and average 96.5 × 10 CTXs/mL. The present CSID hydrogel immunospheres represent a simple, versatile, and time-efficient assay platform for liquid biopsy in the practical setting, enabling us to gain a better understanding of disease-related circulating markers.
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http://dx.doi.org/10.1021/acs.analchem.0c04152DOI Listing
January 2021

Body mass index and body weight change during adjuvant chemotherapy in colon cancer patients: results from the AVANT trial.

Sci Rep 2020 11 10;10(1):19467. Epub 2020 Nov 10.

Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea.

While obesity increases colorectal cancer incidence, there are inconsistent results in the prognostic role of obesity or body weight change on survival. This study investigated the prognostic impact of body weight and weight change in stage III or high risk stage II colon cancer patients. We used data from patients enrolled in the phase III AVANT trial. The AVANT trial investigated the efficacy of adding bevacizumab to standard adjuvant chemotherapy (FOFOX or XELOX). Weight change during the first 6 months of adjuvant chemotherapy was measured. Cox proportional hazard model was used to assess the prognostic influence of body weight and weight change. Among 3451 intention-to-treat population, body weight and weight change was measured in 3449 (99.9%) and 2455 (71.1%) patients, respectively. Among 2455 patients, 651 (26.5%) had weight gain over 5 kg and 179 (7.3%) had weight loss over 5 kg. Weight gain was more frequently observed in Asian and male. Neither baseline BMI nor weight change affected recurrence or survival in the Cox proportional hazard model.
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http://dx.doi.org/10.1038/s41598-020-76643-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655869PMC
November 2020

Phase II Study of Avelumab in Patients with Advanced Hepatocellular Carcinoma Previously Treated with Sorafenib.

Clin Cancer Res 2021 02 2;27(3):713-718. Epub 2020 Nov 2.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Purpose: This study investigated the efficacy and safety of avelumab, an anti-programmed death ligand 1 (PD-L1) antibody, in patients with advanced hepatocellular carcinoma previously treated with sorafenib (NCT03389126).

Patients And Methods: This is a single-arm, single center, phase II trial. Patients with Child-Pugh A score who had at least one measurable lesion were enrolled. Intravenous avelumab 10 mg/kg every 2 weeks was given until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to RECIST v1.1. Secondary endpoints included time to progression (TTP), overall survival (OS), disease control rate (DCR), and safety.

Results: A total of 30 patients were enrolled. After a median follow-up of 13.9 months, 27 progression events and 20 death events occurred. There was no complete response, three (10.0%) partial responses, and 19 patients (63.3%) with stable disease. ORR was 10.0% and DCR was 73.3%. The median TTP and OS was 4.4 and 14.2 months, respectively. PD-L1 expression did not affect avelumab response. Prior duration of sorafenib treatment, when dichotomized by the median 2.7 months, was associated with treatment outcome. TTP (6.5 vs. 1.8 months, = 0.007) and OS (19.0 vs. 7.8 months, = 0.006) were superior in patients with longer sorafenib duration. There was tendency of higher ORR (20.0% vs. 0.0%, = 0.22) in those with longer sorafenib duration. Avelumab was well tolerated with seven grade 3 adverse events and no grade 4 adverse events.

Conclusions: Avelumab showed moderate efficacy and was well tolerated in advanced hepatocellular carcinoma previously treated with sorafenib.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3094DOI Listing
February 2021

Phenotype-based single cell sequencing identifies diverse genetic subclones in CD133 positive cancer stem cells.

Biochem Biophys Res Commun 2021 06 19;558:209-215. Epub 2020 Sep 19.

Department of Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea; Cancer Research Institute, Seoul National University, Seoul, South Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. Electronic address:

Tumor heterogeneity is one of the ongoing huddles in the field of colon cancer therapy. It is evident that there are countless clones which exhibit different phenotypes and therefore, single cell analysis is inevitable. Cancer stem cells (CSCs) are rare cell population within tumor which is known to function in cancer metastasis and recurrence. Although there have been trials to prove intra-tumoral heterogeneity using single cell sequencing, that of CSCs has not been clearly elucidated. Here, we articulate the presence of heterogeneous subclones within CD133 positive cancer stem cells through single cell sequencing. As a proof of principle, we performed phenotype-based high-throughput laser isolation and single cell sequencing (PHLI-seq) of CD133 positive cells in a frozen tumor tissue obtained from a patient with colorectal cancer. The result proved that CD133 positive cells were shown to be heterogeneous both in copy number and mutational profiles. Single cancer stem cell specific mutations such as RNF144A, PAK2, PARP4, ADAM21, HYDIN, KRT38 and CELSR1 could be also detected in liver metastatic tumor of the same patient. Collectively, these data suggest that single cell analysis used to spot subclones with genetic variation within rare population, will lead to new strategies to tackle colon cancer metastasis.
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http://dx.doi.org/10.1016/j.bbrc.2020.09.005DOI Listing
June 2021

Liquid biopsy-based tumor profiling for metastatic colorectal cancer patients with ultra-deep targeted sequencing.

PLoS One 2020 7;15(5):e0232754. Epub 2020 May 7.

Department of Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.

Analyzing cell-free DNA (cfDNA) as a source of circulating tumor DNA is useful for diagnosing or monitoring patients with cancer. However, the concordance between cfDNA within liquid biopsy and genomic DNA (gDNA) within tumor tissue biopsy is still under debate. To evaluate the concordance in a clinical setting, we enrolled 54 patients with metastatic colorectal cancer and analyzed their plasma cfDNA, gDNA from peripheral blood mononuclear cells (PBMC), and gDNA from available matched tumor tissues using ultra-deep sequencing targeting 10 genes (38-kb size) recurrently mutated in colorectal cancer. We first established a highly reliable cut-off value using reference material. The sensitivity of detecting KRAS hotspot mutations in plasma was calculated as 100%, according to digital droplet PCR. We could selectively detect clinically important somatic alterations with a variant allele frequency as low as 0.18%. We next compared somatic mutations of the 10 genes between cfDNA and genomic DNA from tumor tissues and observed an overall 93% concordance rate between the two types of samples. Additionally, the concordance rate of patients with the time interval between liquid biopsy and tumor tissue biopsy within 6 months and no prior exposure to chemotherapy was much higher than those without. The patients with KRAS mutant fragments in plasma had poor prognosis than those without the mutant fragments (33 months vs. 63 months; p<0.05). Consequently, the profiling with our method could achieve highly concordant results and may facilitate the surveillance of the tumor status with liquid biopsy in CRC patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232754PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205246PMC
August 2020

Korean red ginseng for cancer-related fatigue in colorectal cancer patients with chemotherapy: A randomised phase III trial.

Eur J Cancer 2020 05 13;130:51-62. Epub 2020 Mar 13.

Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea. Electronic address:

Background: Cancer-related fatigue (CRF) is a common symptom and has a negative impact on prognosis in cancer patients. CRF could be improved by Korean red ginseng (KRG).

Patients And Methods: For this randomised and double-blinded trial, colorectal cancer patients who received mFOLFOX-6 were randomly assigned to either KRG 2000 mg/day (n = 219) or placebo (n = 219) for 16 weeks. CRF was evaluated using the mean area under the curve (AUC) change from baseline of brief fatigue inventory (BFI) as the primary endpoint. Fatigue-related quality of life, stress, and adverse events were evaluated as secondary endpoints.

Results: In the full analysis group, KRG up to 16 weeks improved CRF by the mean AUC change from baseline of BFI compared to placebo, particularly in "Mood" and "Walking ability" (P = 0.038, P = 0.023, respectively). In the per-protocol group, KRG led to improved CRF in the global BFI score compared with the placebo (P = 0.019). Specifically, there were improvements in "Fatigue right now," "Mood," "Relations with others," "Walking ability," and "Enjoyment of life" at 16 weeks (P = 0.045, P = 0.006, P = 0.028, P = 0.003, P = 0.036, respectively). In subgroups of female patients, ≥60 years old, with high compliance (≥80%) or more baseline fatigue, the beneficial effects of KRG were more enhanced than that of placebo. Although neutropenia was more frequent in KRG than placebo, the incidence of all adverse events was similar.

Conclusions: KRG could be safely combined with mFOLFOX-6 chemotherapy in colorectal cancer patients, and reduced CRF compared with placebo.
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http://dx.doi.org/10.1016/j.ejca.2020.02.018DOI Listing
May 2020

Prognostic factors for survival in colorectal cancer patients with brain metastases undergoing whole brain radiotherapy: multicenter retrospective study.

Sci Rep 2020 03 9;10(1):4340. Epub 2020 Mar 9.

Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea.

Whole brain radiotherapy (WBRT) is a mainstay of the treatment for brain metastases (BM). We evaluated prognostic factors in colorectal cancer (CRC) patients undergoing WBRT for BM. The medical records of 106 CRC patients undergoing WBRT for BM between 2000 and 2014 at three institutions were reviewed. Patient and tumor factors were analyzed to identify the prognostic factors for overall survival (OS) calculated from the date of BM diagnosis to the date of death or last follow-up. Surgical resection of BM was performed in six patients. The dose of WBRT was 30 Gy, and boost radiotherapy or stereotactic radiosurgery (8-23 Gy) was given to 15 patients. Systemic therapy for BM was administered in one patient before WBRT and 26 patients after WBRT. The median follow-up time was 3.9 months (range, 0.4-114.1 months). The median OS time was 3.9 months, and the 1-year OS rate was 18.2%. Older age (>65 years), multiple BM (≥3), elevated level of carcinoembryonic antigen (CEA, >5 ng/ml) at BM diagnosis, and extracranial metastases were adverse prognostic factors for OS. Patient with 0-1 factor showed better OS (at 1 year, 76.9%) than patients with 2 factors (16.7%) or 3-4 factors (4.2%; p < 0.001). In conclusion, we evaluated age, the number of BM, CEA level, and extracranial metastases as the prognostic factors for OS in CRC patients undergoing WBRT. Our result might be useful to develop prognostic models predicting survival for patients whom WBRT is intended for.
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http://dx.doi.org/10.1038/s41598-020-61354-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062910PMC
March 2020

Biochemical and structural analyses reveal that the tumor suppressor neurofibromin (NF1) forms a high-affinity dimer.

J Biol Chem 2020 01 13;295(4):1105-1119. Epub 2019 Dec 13.

NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702

Neurofibromin is a tumor suppressor encoded by the gene, which is mutated in Rasopathy disease neurofibromatosis type I. Defects in lead to aberrant signaling through the RAS-mitogen-activated protein kinase pathway due to disruption of the neurofibromin GTPase-activating function on RAS family small GTPases. Very little is known about the function of most of the neurofibromin protein; to date, biochemical and structural data exist only for its GAP domain and a region containing a Sec-PH motif. To better understand the role of this large protein, here we carried out a series of biochemical and biophysical experiments, including size-exclusion chromatography-multiangle light scattering (SEC-MALS), small-angle X-ray and neutron scattering, and analytical ultracentrifugation, indicating that full-length neurofibromin forms a high-affinity dimer. We observed that neurofibromin dimerization also occurs in human cells and likely has biological and clinical implications. Analysis of purified full-length and truncated neurofibromin variants by negative-stain EM revealed the overall architecture of the dimer and predicted the potential interactions that contribute to the dimer interface. We could reconstitute structures resembling high-affinity full-length dimers by mixing N- and C-terminal protein domains The reconstituted neurofibromin was capable of GTPase activation , and co-expression of the two domains in human cells effectively recapitulated the activity of full-length neurofibromin. Taken together, these results suggest how neurofibromin dimers might form and be stabilized within the cell.
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http://dx.doi.org/10.1074/jbc.RA119.010934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983858PMC
January 2020

Whole-Slide Image Analysis Reveals Quantitative Landscape of Tumor-Immune Microenvironment in Colorectal Cancers.

Clin Cancer Res 2020 02 22;26(4):870-881. Epub 2019 Nov 22.

Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.

Purpose: Despite the well-known prognostic value of the tumor-immune microenvironment (TIME) in colorectal cancers, objective and readily applicable methods for quantifying tumor-infiltrating lymphocytes (TIL) and the tumor-stroma ratio (TSR) are not yet available.

Experimental Design: We established an open-source software-based analytic pipeline for quantifying TILs and the TSR from whole-slide images obtained after CD3 and CD8 IHC staining. Using a random forest classifier, the method separately quantified intraepithelial TILs (iTIL) and stromal TILs (sTIL). We applied this method to discovery and validation cohorts of 578 and 283 stage III or high-risk stage II colorectal cancers patients, respectively, who were subjected to curative surgical resection and oxlaliplatin-based adjuvant chemotherapy.

Results: Automatic quantification of iTILs and sTILs showed a moderate concordance with that obtained after visual inspection by a pathologist. The K-means-based consensus clustering of 197 TIME parameters that showed robustness against interobserver variations caused colorectal cancers to be grouped into five distinctive subgroups, reminiscent of those for consensus molecular subtypes (CMS1-4 and mixed/intermediate group). In accordance with the original CMS report, the CMS4-like subgroup (cluster 4) was significantly associated with a worse 5-year relapse-free survival and proved to be an independent prognostic factor. The clinicopathologic and prognostic features of the TIME subgroups have been validated in an independent validation cohort.

Conclusions: Machine-learning-based image analysis can be useful for extracting quantitative information about the TIME, using whole-slide histopathologic images. This information can classify colorectal cancers into clinicopathologically relevant subgroups without performing a molecular analysis of the tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1159DOI Listing
February 2020

Development of a Nomogram to Predict the Recurrence Score of 21-Gene Prediction Assay in Hormone Receptor-Positive Early Breast Cancer.

Clin Breast Cancer 2020 04 21;20(2):98-107.e1. Epub 2019 Aug 21.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

Introduction: A 21-gene prediction assay (Oncotype DX) is helpful to estimate benefit from adjuvant chemotherapy in patients with hormone receptor-positive, lymph node-negative early breast cancer. This study was conducted to develop a model to estimate high recurrence score (RS) using easily available clinicopathologic parameters in limited-resource countries.

Patients And Methods: Hormone receptor-positive, lymph node-negative early breast cancer patients who underwent Oncotype DX were enrolled onto the training set (n = 192). The risk category range of the RS was the same as in the TAILORx study. The multivariable logistic regression model was used to identify significant variables associated with high RS. The independent validation set (n = 264) was established from patients of a different time period.

Results: The median age in the training set was 47 years, and 78.0% were premenopausal. The number of patients with low RS (< 11), intermediate RS (11-25), and high RS (> 25) were 42 (22.0%), 122 (63.9%), and 27 (14.1%), respectively. High nuclear grade, no progesterone receptor expression, and high Ki-67 were associated with high RS, and these variables were used to construct the nomogram. It had significant discriminatory power in internal validation (area under the curve = 0.856) and in the validation set (area under the curve = 0.828). The calibration plot showed optimal agreement between predicted and actual probabilities in both sets.

Conclusion: A nomogram was successfully developed with 3 simple parameters. The probability of high RS can be easily and conveniently estimated using our nomogram. It might be useful to determine whether or not Oncotype DX is conducted in the TAILORx era. Future large-scale prospective studies are warranted.
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http://dx.doi.org/10.1016/j.clbc.2019.07.010DOI Listing
April 2020

Immune recurrence score using 7 immunoregulatory protein expressions can predict recurrence in stage I-III breast cancer patients.

Br J Cancer 2019 07 11;121(3):230-236. Epub 2019 Jul 11.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Background: Immune cells in the tumour microenvironment play an essential role in tumorigenesis. This study aimed to evaluate the immunoregulatory protein expression of breast cancer and reveal their prognostic role.

Methods: Expression of 10 immune markers (PD-1/PD-L1/PD-L2/IDO/TIM-3/OX40/OX40L/B7-H2/ B7-H3/B7-H4) with known/possible clinical relevance was identified in stromal tumour-infiltrating lymphocytes or tumour tissue of stage I-III breast cancer patients.

Results: A total of 392 patients, including 271(69.1%) luminal A, 36(9.2%) luminal B, 32(8.2%) HER2-positive and 53(13.5%) triple negative disease, were included. Expression of PD-1 and PD-L1 was higher in HER2-positive and triple negative disease. By contrast, expression of TIM-3, OX40 and OX40L were higher in luminal disease. We devised an immune recurrence score (IRS) using seven markers with prognostic value (B7-H2/B7-H3/B7-H4/OX40/OX40L/PD-L1/PD-L2). Patients were classified as high-risk (7.9%), intermediate-risk (67.6%), or low-risk (24.5%). In the multivariate analysis, IRS low-risk (adjusted HR 0.14, p = 0.001) and intermediate-risk (adjusted HR 0.32, p = 0.002) had significantly lower risk of recurrence compared with high-risk. The prognostic role of IRS was maintained in both luminal A and non-luminal A patients.

Conclusions: This study identified immunoregulatory protein expression of breast cancer patients using 10 immune markers. In addition, we devised an IRS which may predict recurrence in stage I-III breast cancer patients.
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http://dx.doi.org/10.1038/s41416-019-0511-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738097PMC
July 2019

Tumor Mutation Burden and Prognosis in Patients with Colorectal Cancer Treated with Adjuvant Fluoropyrimidine and Oxaliplatin.

Clin Cancer Res 2019 10 8;25(20):6141-6147. Epub 2019 Jul 8.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.

Purpose: Recent sequencing studies revealed that a subset of colorectal cancer harbors a significantly higher number of somatic mutations. These hypermutated tumors show distinct clinicopathologic features. However, the prognostic impact of the hypermutated tumors is not clearly established.

Experimental Design: We analyzed tumor mutation burden (TMB) from targeted next-generation sequencing data of 40 major genes in 516 patients with colorectal cancer. TMB was defined as total number of nonsynonymous mutations per tumor. Cutoff value for TMB-high was chosen by which best discriminated relapse-free survival (RFS) using the Contal and O'Quigley method.

Results: In the TCGA data, mutation count of the selected 40 genes reflected the whole exome mutation burden (Pearson correlation = 0.873, < 0.001). In our patient cohort, 8 or more mutations in the 40 genes was defined as TMB-high, which best discriminated RFS. A total of 55 patients (10.7%) had TMB-high. TMB-high tumors were more frequently found in a proximal location (63.6%) and had a higher proportion of N0 disease (30.9%) and MSI-H (49.1%) compared with TMB-low. Most importantly, TMB-high was associated with better 5-year RFS compared with TMB-low (96.3% vs. 79.8%, = 0.005). Although there was significant overlap between TMB-high and MSI-H, MSI-H status was not significantly associated with RFS. Multivariate analysis revealed TMB-high as an independent positive prognostic factor for RFS [adjusted HR, 0.16 (95% confidence interval, 0.04-0.66), = 0.011].

Conclusions: TMB-high is associated with better prognosis in patients with colorectal cancer treated with curative surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1105DOI Listing
October 2019

A First-in-Human Phase I Study of GC1118, a Novel Anti-Epidermal Growth Factor Receptor Antibody, in Patients with Advanced Solid Tumors.

Oncologist 2019 08 4;24(8):1037-e636. Epub 2019 Jun 4.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea

Lessons Learned: GC1118 is a novel fully human anti-epidermal growth factor receptor (EGFR) antibody with unique binding epitopes and different ligand-binding inhibitory activity compared with cetuximab or panitumumab.GC1118 showed promising antitumor activity, especially in patients with colorectal cancer resistant to prior EGFR antibody. Skin toxicities were more common and diarrhea was less frequent compared with other anti-EGFR antibodies.

Background: GC1118 is a novel monoclonal antibody targeting epidermal growth factor receptor (EGFR) with more potent ligand inhibition than cetuximab or panitumumab. We conducted a first-in-human, phase I study of GC118 in patients with refractory solid tumors.

Methods: In the dose escalation part, GC1118 was administered on days 1, 8, 15, and 22, followed by a 2-week rest, during which dose-limiting toxicities (DLTs) were evaluated. In the expansion part, patients were enrolled into three cohorts (Cohort 1 [C1], patients with colorectal cancer [CRC] without prior anti-EGFR treatment; Cohort 2 [C2], patients with CRC with tumors resistant to anti-EGFR therapy; Cohort 3 [C3], EGFR-overexpressing gastric cancer).

Results: In the dose escalation part, 24 patients were treated at five dose levels: 0.3, 1.0, 3.0, 4.0, and 5.0 mg/kg. In the 5.0 mg/kg cohort, two patients experienced DLTs (skin toxicities). The maximum-tolerated dose (MTD) was 4.0 mg/kg. Common adverse events were skin toxicities. In the expansion part, 39 patients were enrolled. In Cohort 1, stable disease (SD) was observed in 58%; in Cohort 2, partial response (PR) 17% and SD 8%; in Cohort 3, PR 8% and SD 17%.

Conclusion: GC1118 showed promising antitumor activity and was well tolerated. Infrequent diarrhea compared with other anti-EGFR antibodies might be advantageous for further development.
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http://dx.doi.org/10.1634/theoncologist.2019-0294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693725PMC
August 2019

Differential effect of concurrent chemotherapy regimen on clinical outcomes of preoperative chemoradiotherapy for locally advanced rectal cancer.

J BUON 2019 Mar-Apr;24(2):470-478

Purpose: The purpose of this study was to evaluate the differential effect of chemotherapy regimen in preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer.

Methods: The medical records of 279 patients who underwent preoperative CRT followed by surgery for cT3/4 rectal cancer from 2003 to 2010 were retrospectively reviewed. Thirty-four patients were treated with one cycle of i.v. bolus 5-fluorouracil (5-FU) during 1st week (group A), 214 patients with two cycles of i.v. bolus 5-FU during 1st and 5th week (group B), and 31 patients with oral capecitabine on the days with radiotherapy (group C). Propensity score matching was performed between three groups.

Results: Median follow-up was 60.1 months. Five-year locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) rates were 91.2, 83.3, 75.0, and 84.5%, respectively. Thirty-one patients per group were allocated to three groups via propensity score matching. On univariate analysis, concurrent chemotherapy regimen was not a significant prognostic factor for survival outcomes in the matched group analysis (OS, p=0.175; DFS, p=0.481; DMFS, p=0.515; LRFS, p=0.456). In addition, there was no significant difference in the sphincter preserving surgery rate, circumferential resection margin status, and pathologic response between three groups (p=0.441, 1.000, 0.818, respectively). As regards to treatment-related toxicity, 9 patients showed grade 3 neutropenia in group B, while there was no grade 3 or higher toxicity in groups A and C.

Conclusion: The concurrent chemotherapy regimen (5-FU #1 vs 5-FU #2 vs capecitabine) did not have a significant effect on treatment outcomes in locally advanced rectal cancer patients receiving neoadjuvant CRT.
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December 2019

Association of pathway mutation with survival after recurrence in colorectal cancer patients treated with adjuvant fluoropyrimidine and oxaliplatin chemotherapy.

BMC Cancer 2019 May 6;19(1):421. Epub 2019 May 6.

Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul, 110-744, South Korea.

Background: Although the prognostic biomarkers associated with colorectal cancer (CRC) survival are well known, there are limited data on the association between the molecular characteristics and survival after recurrence (SAR). The purpose of this study was to assess the association between pathway mutations and SAR.

Methods: Of the 516 patients with stage III or high risk stage II CRC patients treated with surgery and adjuvant chemotherapy, 87 who had distant recurrence were included in the present study. We analyzed the association between SAR and mutations of 40 genes included in the five critical pathways of CRC (WNT, P53, RTK-RAS, TGF-β, and PI3K).

Results: Mutation of genes within the WNT, P53, RTK-RAS, TGF-β, and PI3K pathways were shown in 69(79.3%), 60(69.0%), 57(65.5%), 21(24.1%), and 19(21.8%) patients, respectively. Patients with TGF-β pathway mutation were younger and had higher incidence of mucinous adenocarcinoma (MAC) histology and microsatellite instability-high. TGF-β pathway mutation (median SAR of 21.6 vs. 44.4 months, p = 0.021) and MAC (20.0 vs. 44.4 months, p = 0.003) were associated with poor SAR, and receiving curative resection after recurrence was associated with favorable SAR (Not reached vs. 23.6 months, p <  0.001). Mutations in genes within other critical pathways were not associated with SAR. When MAC was excluded as a covariate, multivariate analysis revealed TGF-β pathway mutation and curative resection after distant recurrence as an independent prognostic factor for SAR. The impact of TGF-β pathway mutations were predicted using the PROVEAN, SIFT, and PolyPhen-2. Among 25 mutations, 23(92.0%)-24(96.0%) mutations were predicted to be damaging mutation.

Conclusions: Mutation in genes within TGF-β pathway may have negative prognostic role for SAR in CRC. Other pathway mutations were not associated with SAR.
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http://dx.doi.org/10.1186/s12885-019-5650-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501409PMC
May 2019

Prognostic role of body mass index is different according to menopausal status and tumor subtype in breast cancer patients.

Breast Cancer Res Treat 2019 Jul 26;176(2):453-460. Epub 2019 Apr 26.

Department of Preventive Medicine, The Catholic University of Korea, Seoul, South Korea.

Purpose: Although controversial, obesity and underweight may have a negative impact on breast cancer outcome. However, the relationship between body mass index (BMI) and breast cancer outcomes according to tumor subtype and menopausal status remains unclear.

Methods: This study investigated the association between BMI and breast cancer outcome in stage I-III breast cancer patients. The relationships were further evaluated according to tumor subtype and menopausal status.

Results: A total of 5919 patients, 3475 (58.7%) hormone receptor (HR)(+) human epidermal growth factor receptor 2 (HER2)(-), 608 (10.3%) HR(+)HER2(+), 621 (10.5%) HR(-)HER2(+), and 1079 (18.2%) HR(-)HER2(-) were included. Underweight and obesity had a negative impact on relapse-free survival but did not affect overall survival. Importantly, the prognostic role of BMI was different according to tumor subtype and menopausal status. In HR(+)HER2(-) patients, underweight was associated with poor relapse-free survival and overall survival in pre-menopausal women. In contrast, obesity had negative impact on relapse-free survival and overall survival in HR(+)HER2(-) post-menopausal patients. Underweight may have a negative prognostic role in HR(+)HER2(+) patients. However, BMI did not impact the outcome of HR(-)HER2(+) and HR(-)HER2(-) patients.

Conclusions: The impact of BMI on breast cancer outcome was dependent on tumor subtype and menopausal status. In HR(+)HER2(-) patients, underweight and obesity had a negative prognostic role in pre-menopausal and post-menopausal women, respectively. These findings in Asian population should be further evaluated and compared in Western population.
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http://dx.doi.org/10.1007/s10549-019-05249-1DOI Listing
July 2019

p53 expression status is associated with cancer-specific survival in stage III and high-risk stage II colorectal cancer patients treated with oxaliplatin-based adjuvant chemotherapy.

Br J Cancer 2019 04 21;120(8):797-805. Epub 2019 Mar 21.

Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.

Background: We attempted to elucidate whether p53 expression or TP53 mutation status was associated with cancer-specific survival in adjuvant FOLFOX-treated patients with stage III or high-risk stage II colorectal cancer (CRC).

Methods: We analysed CRCs (N = 621) for the presence of TP53 alterations and for p53 expression, using targeted resequencing and immunohistochemistry. CRCs were grouped into four subsets according to the p53 expression status, which included p53-no, mild, moderate and strong expression.

Results: The distributions of CRCs were 19.85, 11.05, 17.7% and 51.5% in the p53-no, mild, moderate and strong expression groups, respectively. Cases in the p53-mild to moderate expression group were associated with a more frequent proximal location, undifferentiated histology, lower N category, extraglandular mucin production, microsatellite instability, CIMP-P1, CK7 expression and decreased CDX2 expression compared with those of cases of the p53-no expression and p53-strong expression groups. According to survival analysis, the p53-mild expression group showed a poor 5-year relapse-free survival (hazard ratio (HR): 2.71, 95% confidence interval (CI) = 1.60-4.60, P < 0.001) and poor 5-year cancer-specific survival (HR: 2.90, 95% CI = 1.28-6.57, P = 0.011).

Conclusions: p53-mild expression status was found to be an independent prognostic marker in adjuvant FOLFOX-treated patients with stage III and high-risk stage II CRC.
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http://dx.doi.org/10.1038/s41416-019-0429-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474280PMC
April 2019

Results of re-irradiation for pelvic recurrence in anorectal cancer patients.

Br J Radiol 2019 May 29;92(1097):20180794. Epub 2019 Mar 29.

6 Department of Radiation Oncology, Seoul National University College of Medicine , Seoul , Republic of Korea.

Objective: To evaluate outcomes and toxicity profiles after re-irradiation in patients with pelvic recurrence of anorectal cancer.

Methods: 25 anorectal cancer patients who received re-irradiation for pelvic recurrence between 2005 and 2015 were included. For initial treatment, all patients underwent surgical resection and preoperative or postoperative radiotherapy.

Results: The median follow-up duration was 21.5 months (range, 2.9-84.4). After a median of 43.3 months (range, 11.7-218.5), patients received re-irradiation with a median dose of 45 Gy (range, 36-60). The equivalent dose in 2 Gy fractions (EQD2) of re-irradiation-calculated using α/β = 10 Gy-ranged from 34.5 to 84.0 Gy (median, 46.4). Surgical resection was performed for 11 patients, and 14 patients received concurrent chemotherapy with re-irradiation. The 3-year local progression-free survival was 29.7%. The 3-year overall survival was 49.7%. Concurrent chemotherapy with re-irradiation and re-irradiation doses >50 Gy EQD2 were significant prognostic factors for local progression free survival and overall survival according to multivariate analysis. 90% (9 of 10) of patients with symptoms had improvement after re-irradiation. Among 23 patients available for evaluation of late toxicity, 12 developed late toxicities. There were no Grade 4 late toxicities, and 6 patients had Grade 3 late toxicities (small bowel obstruction, bowel perforation and fistula).

Conclusion: Re-irradiation for pelvic recurrence of anorectal cancer improved symptoms of patients but the rate of late toxicity was high. Further investigation for patient selection is required.

Advances In Knowledge: Re-irradiation could be considered as a possible option for pelvic recurrence of anorectal cancer in selected patients.
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http://dx.doi.org/10.1259/bjr.20180794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580908PMC
May 2019

Pruritus in Patients Under Targeted Anticancer Therapy: A Multidimensional Analysis Using the 5-D Itch Scale.

Acta Derm Venereol 2019 Apr;99(4):435-441

Department of Dermatology, Seoul National University Hospital, Seoul, Korea.

Pruritus is a very common symptom in patients, undergoing targeted anticancer therapy. However, the characteristics of pruritus, according to the targeted anticancer agents, are still unclear. The objective of this study was to determine the characteristics of pruritus, induced by targeted anticancer agents, using a questionnaire-based survey. The survey was administered to cancer patients currently receiving anticancer agents. Medical records were also reviewed. A total of 374 cancer patients completed the survey, of which 108 were treated with the targeted therapy. A total of 205 patients had pruritus, of which 66 were under the targeted therapy. Epidermal growth factor receptor inhibitor (EGFRI) users showed the highest prevalence rate of itching and numeric rating scale score for itching. The 5-D itch score was also highest among users of EGFRIs. In conclusion, patients receiving EGFRIs suffer from severe pruritus frequently. They not only experienced long lasting and intense itching, causing sleep discomfort, but also developed itching at specific body sites.
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http://dx.doi.org/10.2340/00015555-3129DOI Listing
April 2019

Prognostic effects of abnormal DNA damage response protein expression in breast cancer.

Breast Cancer Res Treat 2019 May 22;175(1):117-127. Epub 2019 Jan 22.

Translational Medicine, Seoul National University College of Medicine, Seoul, Korea.

Purpose: We aimed to explore the expression of DNA damage response machinery proteins and their integrated prognostic value in different subgroups of breast cancer.

Methods: Expression of NBS1, BRCA1, BRCA2, ATM, and p53 was determined by immunohistochemistry in 419 surgically resected breast tumors.

Results: Loss of NBS1, BRCA1, ATM, and abnormal p53 expression was significantly associated with lower disease-free survival rates. Abnormal DNA damage response protein expression, defined as loss of any one of NBS1, BRCA1, ATM, and/or abnormal p53 expression, was observed in 258 of 399 evaluable cases (64.7%) and was significantly associated with higher tumor grade, larger tumor size, and ER-negative, and/or PR-negative status. Most patients with luminal B (86.1%), HER2-enriched (94.4%), and triple-negative (86.8%) breast cancers had abnormal DNA damage response protein expression. In contrast, abnormal DNA damage response protein expression was found in only 53.8% of luminal A tumors. Abnormal DNA damage response protein expression was associated with significantly lower 5-year disease-free survival rates in all patients (95.6% vs. 84.8%, p = 0.001), as well as in the luminal A subgroup (97.4% vs. 89.0%, p = 0.011). In multivariate analysis, abnormal DNA damage response protein expression remained an independent predictor of shorter disease-free survival for luminal A subtype (hazard ratio 3.14, 95% confidence interval 1.16-8.47; p = 0.024).

Conclusion: Abnormal DNA damage response protein expression is found in most luminal B and HER2-enriched breast cancers as frequently as in triple-negative breast cancer. In the luminal A subtype, abnormal DNA damage response protein expression is an independent prognostic marker.
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http://dx.doi.org/10.1007/s10549-019-05128-9DOI Listing
May 2019

Impact of Mucin Proportion in the Pretreatment MRI on the Outcomes of Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy.

Cancer Res Treat 2019 Jul 20;51(3):1188-1197. Epub 2018 Dec 20.

Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.

Purpose: The purpose of this study was to evaluate treatment response to neoadjuvant chemoradiotherapy (CRT) with regard to mucin status in pathology and pretreatment magnetic resonance imaging (MRI) in locally advanced rectal cancer.

Materials And Methods: Between 2003 and 2011, 306 patients with locally advanced rectal cancer received neoadjuvant CRT followed by surgery, and mucinous adenocarcinoma (MAC) was found in 27 (8.8%). All MAC patients had MRI before and after CRT and mucin proportion at MRI was measured. Therapeutic response was assessed by pathology after total mesorectal excision. To determine the optimal cut-off for mucin proportion in predicting good CRT response (near total or total regression) and negative circumferential resection margin (CRM), the receiver-operating characteristic analysis was performed.

Results: After neoadjuvant CRT, overall downstaging occurred in 44.4% of MAC and 72.4% of non-MAC (p=0.001), and positive CRM (≤1 mm) was observed more frequently in MAC (p<0.001). The optimal threshold for treatment response was 30% for mucin proportion, and there are nine with low mucin proportion (<30%) and 18 with high mucin proportion (≥30%) in pretreatment MRI. Negative CRM and tumor downstaging occurred more common in patients with mucin <30%, although statistically insignificant (p=0.071 and p=0.072, respectively). Regarding oncologic outcomes, lower mucin proportion in pretreatment MRI was associated with better disease-free and overall survival in MAC group (p=0.092 and 0.056, respectively), but the difference did not reach statistical significance.

Conclusion: Poor treatment outcome with neoadjuvant CRT was observed in patients with MAC, especially those with high mucin proportion at pretreatment MRI.
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http://dx.doi.org/10.4143/crt.2018.434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639202PMC
July 2019

A Single Arm, Phase II Study of Simvastatin Plus XELOX and Bevacizumab as First-Line Chemotherapy in Metastatic Colorectal Cancer Patients.

Cancer Res Treat 2019 Jul 21;51(3):1128-1134. Epub 2018 Nov 21.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: Simvastatin has demonstrated anti-tumor activity in preclinical studies via tumor cell senescence, apoptosis, and anti-angiogenesis. This phase II trial evaluated the efficacy and toxicity profile of conventional XELOX and bevacizumab chemotherapy plus simvastatin in metastatic colorectal cancer patients (MCRC).

Materials And Methods: Patients with MCRC received first-line XELOX in 3-week treatment cycles of intravenous oxaliplatin 130 mg/m2 plus bevacizumab 7.5 mg/kg (day 1), followed by oral capecitabine 1,000 mg/m2 twice daily (day 1-14). Simvastatin 80 mg tablets were taken orally once daily every day during the period of chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, duration of response, overall survival (OS), time to progression, and toxicity.

Results: From January 2014 to April 2015, 60 patients were enrolled and 55 patients were evaluable for tumor response. The median follow-up duration was 30.1 months (range, 28.5 to 31.7 months). The median PFS was 10.4 months (95% confidence interval [CI], 9.6 to 11.1). The median OS of all patients was 19.0 months (95% CI, 11.9 to 26.0). The disease-control rate and overall response rate were 88.3% (95% CI, 74 to 96) and 58.3% (95% CI, 44 to 77), respectively, by intent-to-treat protocol analysis. There was one complete response and 34 partial responses. One patient experienced grade 3 creatine kinase elevation and liver enzyme elevation.

Conclusion: Based on the current study, the addition of 80 mg simvastatin to XELOX and bevacizumab showed comparable clinical efficacy in patients with MCRC as first-line chemotherapy and did not increase toxicity.
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http://dx.doi.org/10.4143/crt.2018.379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639242PMC
July 2019
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