Publications by authors named "Tae-You Kim"

354 Publications

Radioembolization With Chemotherapy for Colorectal Liver Metastases: A Randomized, Open-Label, International, Multicenter, Phase III Trial.

J Clin Oncol 2021 Sep 20:JCO2101839. Epub 2021 Sep 20.

Department of Radiology, Section of Interventional Radiology, Northwestern University, Chicago, IL.

Purpose: To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM).

Methods: In this international, multicenter, open-label phase III trial, patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line therapy were randomly assigned 1:1 to receive second-line chemotherapy with or without TARE. The two primary end points were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded independent central review. Random assignment was performed using a web- or voice-based system stratified by unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line chemotherapy, and mutation status.

Results: Four hundred twenty-eight patients from 95 centers in North America, Europe, and Asia were randomly assigned to chemotherapy with or without TARE; this represents the intention-to-treat population and included 215 patients in the TARE plus chemotherapy group and 213 patients in the chemotherapy alone group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided = .0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 1-sided < .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided = .0019) for the TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided = .7229) with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently with TARE (68.4% 49.3%). Both groups received full chemotherapy dose intensity.

Conclusion: The addition of TARE to systemic therapy for second-line CLM led to longer PFS and hPFS. Further subset analyses are needed to better define the ideal patient population that would benefit from TARE.
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http://dx.doi.org/10.1200/JCO.21.01839DOI Listing
September 2021

Radiation Response Prediction Model based on Integrated Clinical and Genomic Data Analysis.

Cancer Res Treat 2021 Aug 24. Epub 2021 Aug 24.

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

Purpose: The value of the genomic profiling by targeted gene-sequencing on radiation therapy response prediction was evaluated through integrated analysis including clinical information. Radiation response prediction model was constructed based on the analyzed findings.

Materials And Methods: Patients who had the tumor sequenced using institutional cancer panel after informed consent and received radiotherapy for the measurable disease served as the target cohort. Patients with irradiated tumor locally controlled for more than 6 months after radiotherapy were defined as the durable local control (DLC) group, otherwise, non-durable local control (NDLC) group. Significant genomic factors and domain knowledge were used to develop the Bayesian Network model to predict radiotherapy response.

Results: Altogether, 88 patients were collected for analysis. Of those, 41 (43.6%) and 47 (54.4%) patients were classified as the NDLC and DLC group, respectively. Somatic mutations of NOTCH2 and BCL were enriched in the NDLC group, whereas, mutations of CHEK2, MSH2, and NOTCH1 were more frequently found in the DLC group. Altered DNA repair pathway was associated with better local failure-free survival (HR 0.40, 95%CI 0.19-0.86, p=0.014). Smoking somatic signature was found more frequently in the DLC group. AUC of the Bayesian Network model predicting probability of 6-month local control was 0.83.

Conclusion: Durable radiation response was associated with alterations of DNA repair pathway and smoking somatic signature. Bayesian network model could provide helpful insights for high precision radiotherapy. However, these findings should be verified in prospective cohort for further individualization.
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http://dx.doi.org/10.4143/crt.2021.759DOI Listing
August 2021

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

Sci Rep 2021 Aug 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

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study.

J Clin Oncol 2021 Sep 22;39(27):2991-3001. Epub 2021 Jul 22.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348).

Patients And Methods: Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles.

Results: A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively.

Conclusion: All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.
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http://dx.doi.org/10.1200/JCO.20.03555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445563PMC
September 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 Jul 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

Ramucirumab in patients with previously treated advanced hepatocellular carcinoma: Impact of liver disease aetiology.

Liver Int 2021 Jun 26. Epub 2021 Jun 26.

Massachusetts General Hospital Cancer Center, Boston, MA, USA.

Background & Aims: Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease with diverse underlying aetiologies. REACH/REACH-2 were global phase III studies investigating ramucirumab in advanced HCC (aHCC) following sorafenib treatment. We performed an exploratory analysis of outcomes by liver disease aetiology and baseline serum viral load.

Methods: Meta-analysis was conducted in patients with aHCC and alpha-fetoprotein (AFP) ≥400 ng/mL (N = 542) from REACH/REACH-2 trials. Individual patient-level data were pooled with results reported by aetiology subgroup (hepatitis B [HBV] or C [HCV] and Other). Pre-treatment serum HBV DNA and HCV RNA were quantified using Roche COBAS AmpliPrep/COBAS TaqMan. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox proportional hazard model (stratified by study).

Results: Baseline characteristics were generally balanced between arms in each subgroup (HBV: N = 225, HCV: N = 127, Other: N = 190). No significant difference in treatment effect by aetiology subgroup was detected (OS interaction P-value = .23). Median OS (ramucirumab vs placebo) in months was 7.7 versus 4.5 (HR 0.74, 95% CI 0.55-0.99) for HBV, 8.2 versus 5.5 (HR 0.82, 95% CI 0.55-1.23) for HCV and 8.5 versus 5.4 (HR 0.56, 95% CI 0.40-0.79) for Other. Ramucirumab showed similar overall safety profiles across subgroups. Worst outcomes were noted in patients with a detectable HBV load. Use of HBV antiviral therapy, irrespective of viral load, was beneficial for survival, liver function and liver-specific adverse events.

Conclusions: Ramucirumab improved survival across aetiology subgroups with a tolerable safety profile, supporting its use in patients with aHCC and elevated AFP.
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http://dx.doi.org/10.1111/liv.14994DOI Listing
June 2021

Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial.

Lancet Oncol 2021 07 27;22(7):991-1001. Epub 2021 May 27.

Department of Medical Oncology, Gustave Roussy, Villejuif, France.

Background: Understanding patients' experience of cancer treatment is important. We aimed to evaluate patient-reported outcomes (PROs) with atezolizumab plus bevacizumab versus sorafenib in patients with advanced hepatocellular carcinoma in the IMbrave150 trial, which has already shown significant overall survival and progression-free survival benefits with this combination therapy.

Methods: We did an open-label, randomised, phase 3 trial in 111 hospitals and cancer centres across 17 countries or regions. We included patients aged 18 years or older with systemic, treatment-naive, histologically, cytologically, or clinically confirmed unresectable hepatocellular carcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with disease that was not amenable to curative surgical or locoregional therapies, or progressive disease after surgical or locoregional therapies. Participants were randomly assigned (2:1; using permuted block randomisation [blocks of six], stratified by geographical region; macrovascular invasion, extrahepatic spread, or both; baseline alpha-fetoprotein concentration; and ECOG performance status) to receive 1200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously once every 3 weeks or 400 mg sorafenib orally twice a day, until loss of clinical benefit or unacceptable toxicity. The independent review facility for tumour assessment was masked to the treatment allocation. Previously reported coprimary endpoints were overall survival and independently assessed progression-free survival per Response Evaluation Criteria in Solid Tumors 1.1. Prespecified secondary and exploratory analyses descriptively evaluated treatment effects on patient-reported quality of life, functioning, and disease symptoms per the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (QLQ-C30) and quality-of-life questionnaire for hepatocellular carcinoma (QLQ-HCC18). Time to confirmed deterioration of PROs was analysed in the intention-to-treat population; all other analyses were done in the PRO-evaluable population (patients who had a baseline PRO assessment and at least one assessment after baseline). The trial is ongoing; enrolment is closed. This trial is registered with ClinicalTrials.gov, NCT03434379.

Findings: Between March 15, 2018, and Jan 30, 2019, 725 patients were screened and 501 patients were enrolled and randomly assigned to atezolizumab plus bevacizumab (n=336) or sorafenib (n=165). 309 patients in the atezolizumab plus bevacizumab group and 145 patients in the sorafenib group were included in the PRO-evaluable population. At data cutoff (Aug 29, 2019) the median follow-up was 8·6 months (IQR 6·2-10·8). EORTC QLQ-C30 completion rates were 90% or greater for 23 of 24 treatment cycles in both groups (range 88-100% in the atezolizumab plus bevacizumab group and 80-100% in the sorafenib group). EORTC QLQ-HCC18 completion rates were 90% or greater for 20 of 24 cycles in the atezolizumab plus bevacizumab group (range 88-100%) and 21 of 24 cycles in the sorafenib group (range 89-100%). Compared with sorafenib, atezolizumab plus bevacizumab reduced the risk of deterioration on all EORTC QLQ-C30 generic cancer symptom scales that were prespecified for analysis (appetite loss [hazard ratio (HR) 0·57, 95% CI 0·40-0·81], diarrhoea [0·23, 0·16-0·34], fatigue [0·61, 0·46-0·81], pain [0·46, 0·34-0·62]), and two of three EORTC QLQ-HCC18 disease-specific symptom scales that were prespecified for analysis (fatigue [0·60, 0·45-0·80] and pain [0·65, 0·46-0·92], but not jaundice [0·76, 0·55-1·07]). At day 1 of treatment cycle five (after which attrition in the sorafenib group was more than 50%), the mean EORTC QLQ-C30 score changes from baseline in the atezolizumab plus bevacizumab versus sorafenib groups were: -3·29 (SD 17·56) versus -5·83 (20·63) for quality of life, -4·02 (19·42) versus -9·76 (21·33) for role functioning, and -3·77 (12·82) versus -7·60 (15·54) for physical functioning.

Interpretation: Prespecified analyses of PRO data showed clinically meaningful benefits in terms of patient-reported quality of life, functioning, and disease symptoms with atezolizumab plus bevacizumab compared with sorafenib, strengthening the combination therapy's positive benefit-risk profile versus that of sorafenib in patients with unresectable hepatocellular carcinoma.

Funding: F Hoffmann-La Roche and Genentech.
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http://dx.doi.org/10.1016/S1470-2045(21)00151-0DOI Listing
July 2021

Randomised Phase 1b/2 trial of tepotinib vs sorafenib in Asian patients with advanced hepatocellular carcinoma with MET overexpression.

Br J Cancer 2021 Jul 10;125(2):200-208. Epub 2021 May 10.

Medical Oncology Department, PLA Cancer Center, Nanjing Bayi Hospital, Nanjing, China.

Background: This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression.

Methods: In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP).

Results: In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26-0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib.

Conclusions: Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression.

Trial Registration: ClinicalTrials.gov NCT01988493.
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http://dx.doi.org/10.1038/s41416-021-01380-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292411PMC
July 2021

Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): 10-year follow-up of an open-label, non-inferiority, randomised controlled trial.

Lancet Gastroenterol Hepatol 2021 07 23;6(7):569-577. Epub 2021 Apr 23.

Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, South Korea.

Background: Laparoscopic surgery has been widely used for rectal cancer; however, its long-term outcomes remain controversial. This study aimed to assess the long-term oncological safety of laparoscopic surgery for rectal cancer using 10-year follow-up data of the Comparison of Open versus laparoscopic surgery for mid or low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial.

Methods: The COREAN trial is a, open-label, non-inferiority, randomised controlled trial. Eligible participants were aged 18-80 years, had cT3N0-2M0 middle or low rectal cancer with lesions located within 9 cm of the anal verge, and had been treated with preoperative chemoradiotherapy. Patients were randomly assigned (1:1) to open or laparoscopic surgery with a computer-generated random allocation sequence with a random permuted block design. Neither patients nor clinicians were masked to treatment assignment. Open or laparoscopic total mesorectal excision was done 6-8 weeks after the administration of preoperative concurrent chemoradiotherapy (fluoropyrimidines alone, doublet therapy, or triplet therapy) at a dose of 50·5 Gy over 5·5 weeks. Postoperative adjuvant chemotherapy was administered for 4 months. The primary endpoint of 3-year disease-free survival was published previously. Here, we report 10-year overall survival, disease-free survival, and local recurrence. Analyses were done in the modified intention-to-treat population of all participants who were randomly assigned and provided follow-up data. This study is registered with ClinicalTrials.gov, NCT00470951.

Findings: Of the 340 patients enrolled in the COREAN trial between April 4, 2006, and Aug 26, 2009 (170 patients in each group), two patients in the laparoscopic surgery group moved abroad and were lost to follow-up, so were not included in this 10-year analysis. The median duration of follow-up was 143 months (IQR 122-156). No differences were observed in 10-year overall survival (74·1% [95% CI 66·8-80·0] in the open surgery group vs 76·8% [69·6-82·5] in the laparoscopic surgery group; p=0·44), 10-year disease-free survival (59·3% [51·1-66·5] vs 64·3% [56·0-71·5]; p=0·20), or 10-year local recurrence (8·9% [5·2-15·0] vs 3·4% [1·4-7·9]; p=0·050) between the open surgery and laparoscopic surgery groups at 10 years after surgery. The stratified hazard ratios, adjusted for ypT and ypN classification and tumour regression grade, for open surgery versus laparoscopic surgery were 0·94 (95% CI 0·63-1·43) for overall survival, 1·05 (0·74-1·49) for disease-free survival, and 2·22 (0·78-6·34) for local recurrence.

Interpretation: The 10-year follow-up of the COREAN trial confirms the long-term oncological safety of laparoscopic surgery in patients with rectal cancer treated with preoperative chemoradiotherapy. Similar to open surgery, laparoscopic surgery does not compromise long-term survival outcomes in rectal cancer when performed by well trained surgeons.

Funding: National Cancer Center, Goyang, South Korea.
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http://dx.doi.org/10.1016/S2468-1253(21)00094-7DOI Listing
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 Oct 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

Targeted next-generation sequencing-based detection of microsatellite instability in colorectal carcinomas.

PLoS One 2021 1;16(2):e0246356. Epub 2021 Feb 1.

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

In the present study, we developed a computational method and panel markers to assess microsatellite instability (MSI) using a targeted next-generation sequencing (NGS) platform and compared the performance of our computational method, mSILICO, with that of mSINGS to detect MSI in CRCs. We evaluated 13 CRC cell lines, 84 fresh and 119 formalin-fixed CRC tissues (including 61 MSI-high CRCs and 155 microsatellite-stable CRCs) and tested the classification performance of the two methods on 23, 230, and 3,154 microsatellite markers. For the fresh tissue and cell line samples, mSILICO showed a sensitivity of 100% and a specificity of 100%, regardless of the number of panel markers, whereas for the formalin-fixed tissue samples, mSILICO exhibited a sensitivity of up to 100% and a specificity of up to 100% with three differently sized panels ranging from 23 to 3154. These results were similar to those of mSINGS. With the application of mSILICO, the small panel of 23 markers had a sensitivity of ≥95% and a specificity of 100% in cell lines/fresh tissues and formalin-fixed tissues of CRC. In conclusion, we developed a new computational method and microsatellite marker panels for the determination of MSI that does not require paired normal tissues. A small panel could be integrated into the targeted NGS panel for the concurrent analysis of single nucleotide variations and MSI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246356PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850495PMC
July 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 2020 Dec 30. 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 1,000mg/m2 on days 1 and 8 and cisplatin 60mg/m2 on day 1 every 3 weeks for 2 cycles, followed by chemoradiotherapy (50.4Gy/28Fx's) with weekly gemcitabine (300mg/m2/week), and then gemcitabine 1,000mg/m2 on day 1, 8 every 3 weeks for 4 cycles. The primary endpoint was one-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], 11.6-18.4) and 33.0 months (95% CI, 21.8-44.2), 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 DFS 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
December 2020

Blood-Based Detection of Colorectal Cancer Using Cancer-Specific DNA Methylation Markers.

Diagnostics (Basel) 2020 Dec 31;11(1). Epub 2020 Dec 31.

Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.

Cancer tissues have characteristic DNA methylation profiles compared with their corresponding normal tissues that can be utilized for cancer diagnosis with liquid biopsy. Using a genome-scale DNA methylation approach, we sought to identify a panel of DNA methylation markers specific for cell-free DNA (cfDNA) from patients with colorectal cancer (CRC). By comparing DNA methylomes between CRC and normal mucosal tissues or blood leukocytes, we identified eight cancer-specific methylated loci (, , , , , , , and ) and developed a five-marker panel (, , , , and ) that detected CRC in liquid biopsies with a high sensitivity and specificity with a droplet digital MethyLight assay. In a set of cfDNA samples from CRC patients ( = 117) and healthy volunteers ( = 60), a panel of five markers on the platform of the droplet digital MethyLight assay detected stages I-III and stage IV CRCs with sensitivities of 45.9% and 95.7%, respectively, and a specificity of 95.0%. The number of detected markers was correlated with the cancer stage, perineural invasion, lymphatic emboli, and venous invasion. Our five-marker panel with the droplet digital MethyLight assay showed a high sensitivity and specificity for the detection of CRC with cfDNA samples from patients with metastatic CRC.
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http://dx.doi.org/10.3390/diagnostics11010051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823774PMC
December 2020

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

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial.

JAMA Oncol 2020 Nov 12;6(11):e204564. Epub 2020 Nov 12.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Importance: Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy.

Objective: To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib.

Design, Setting, And Participants: CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C).

Interventions: Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C).

Main Outcomes And Measures: Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1).

Results: Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis).

Conclusions And Relevance: In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study.

Trial Registration: ClinicalTrials.gov Identifier: NCT01658878.
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http://dx.doi.org/10.1001/jamaoncol.2020.4564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530824PMC
November 2020

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

Effectiveness of nivolumab versus regorafenib in hepatocellular carcinoma patients who failed sorafenib treatment.

Clin Mol Hepatol 2020 07 28;26(3):328-339. Epub 2020 May 28.

Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Background/aims: Several treatment options are currently available for patients with hepatocellular carcinoma (HCC) failing previous sorafenib treatment. We aimed to compare the effectiveness of regorafenib and nivolumab in these patients.

Methods: Consecutive HCC patients who received regorafenib or nivolumab after failure of sorafenib treatment were included. Primary endpoint was overall survival (OS) and secondary endpoints were time to progression, tumor response rate, and adverse events. Inverse probability of treatment weighting (IPTW) using the propensity score was conducted to reduce treatment selection bias.

Results: Among 150 study patients, 102 patients received regorafenib and 48 patients received nivolumab. Median OS was 6.9 (95% confidence interval [CI], 3.0-10.8) months for regorafenib and 5.9 (95% CI, 3.7-8.1) months for nivolumab (P=0.77 by log-rank test). In multivariable analysis, nivolumab was associated with prolonged OS (vs. regorafenib: adjusted hazard ratio [aHR], 0.54; 95% CI, 0.30-0.96; P=0.04). Time to progression was not significantly different between groups (nivolumab vs. regorafenib: aHR, 0.82; 95% CI, 0.51-1.30; P=0.48). HRs were maintained after IPTW. Objective response rates were 5.9% and 16.7% in patients treated with regorafenib and nivolumab, respectively (P=0.04).

Conclusion: After sorafenib failure, the use of nivolumab may be associated with improved OS and better objective response rate as compared to using regorafenib.
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http://dx.doi.org/10.3350/cmh.2019.0049nDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364358PMC
July 2020

Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer.

Nat Genet 2020 06 25;52(6):594-603. Epub 2020 May 25.

Systems Biology and Data Analytics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations. Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies.
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http://dx.doi.org/10.1038/s41588-020-0636-zDOI Listing
June 2020

Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.

N Engl J Med 2020 05;382(20):1894-1905

From the Jonsson Comprehensive Cancer Center, Geffen School of Medicine at UCLA, Los Angeles (R.S.F.), the City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte (D.L.), and Genentech, South San Francisco (W.V., S.H., Y.W.) - all in California; the People's Liberation Army Cancer Center, Jinling Hospital, Nanjing (S.Q.), and Roche Product Development (D.-Z.X., J.L., C.H.) and Jiahui International Cancer Center, Jiahui Health (A.X.Z.), Shanghai - all in China; National Cancer Center Hospital East, Kashiwa (M.I.), and Kindai University Faculty of Medicine, Osaka (M.K.) - both in Japan; University Medical Center Mainz, Mainz, Germany (P.R.G.); Gustave Roussy Cancer Center, Paris-Saclay University, Villejuif (M.D.), and University Hospital La Croix-Rousse, Lyon (P.M.) - both in France; Seoul National University College of Medicine (T.-Y.K.) and Samsung Medical Center, Sungkyunkwan University School of Medicine (H.Y.L.) - both in Seoul, South Korea; N.N. Blokhin Russian Cancer Research Center, Moscow (V.B.); the University of Texas M.D. Anderson Cancer Center, Houston (A.O.K.); Hoffmann-La Roche, Mississauga, ON, Canada (S.M.); Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston (A.X.Z.); and the National Taiwan University Cancer Center and National Taiwan University Hospital, Taipei (A.-L.C.).

Background: The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma.

Methods: In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).

Results: The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent.

Conclusions: In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT03434379.).
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http://dx.doi.org/10.1056/NEJMoa1915745DOI Listing
May 2020

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

A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair-Deficient/Microsatellite Instability-High or POLE-Mutated Metastatic or Unresectable Colorectal Cancer.

Cancer Res Treat 2020 Oct 24;52(4):1135-1144. Epub 2020 Apr 24.

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

Purpose: We evaluated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with metastatic or unresectable colorectal cancer (mCRC) with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations.

Materials And Methods: In this prospective, open-label, multicenter phase II study, 33 patients with mCRC harboring dMMR/MSI-H or POLE mutations after failure of ≥1st-line chemotherapy received avelumab 10 mg/kg every 2 weeks. dMMR/MSI-H was confirmed with immunohistochemical staining (IHC) by loss of expression of MMR proteins or polymerase chain reaction (PCR) for microsatellite sequences. POLE mutation was confirmed by next-generation sequencing (NGS). The primary endpoint was the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors ver. 1.1.

Results: The median age was 60 years, and 78.8% were male. Thirty patients were dMMR/MSI-H and three had POLE mutations. The ORR was 24.2%, and all of the responders were dMMR/MSI-H. For 21 patients with MSI-H by PCR or NGS, the ORR was 28.6%. At a median follow-up duration of 16.3 months, median progression-free survival and overall survival were 3.9 and 13.2 months in all patients, and 8.1 months and not reached, respectively, in patients with MSI-H by PCR or NGS. Dose interruption and discontinuation due to treatment-related adverse events occurred in four and two patients, respectively, with no treatment-related deaths.

Conclusion: Avelumab displayed antitumor activity with manageable toxicity in patients with previously treated mCRC harboring dMMR/MSI-H. Diagnosis of dMMR/MSI-H with PCR or NGS could be complementary to IHC to select patients who would benefit from immunotherapy.
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http://dx.doi.org/10.4143/crt.2020.218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577804PMC
October 2020

Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours.

Br J Cancer 2020 05 2;122(11):1630-1637. Epub 2020 Apr 2.

The University of Texas Southwestern Medical Center, Dallas, TX, USA.

Background: In this first-in-human, Phase 1 study of a microRNA-based cancer therapy, the recommended Phase 2 dose (RP2D) of MRX34, a liposomal mimic of microRNA-34a (miR-34a), was determined and evaluated in patients with advanced solid tumours.

Methods: Adults with various solid tumours refractory to standard treatments were enrolled in 3 + 3 dose-escalation cohorts and, following RP2D determination, expansion cohorts. MRX34, with oral dexamethasone premedication, was given intravenously daily for 5 days in 3-week cycles.

Results: Common all-cause adverse events observed in 85 patients enrolled included fever (% all grade/G3: 72/4), chills (53/14), fatigue (51/9), back/neck pain (36/5), nausea (36/1) and dyspnoea (25/4). The RP2D was 70 mg/m for hepatocellular carcinoma (HCC) and 93 mg/m for non-HCC cancers. Pharmacodynamic results showed delivery of miR-34a to tumours, and dose-dependent modulation of target gene expression in white blood cells. Three patients had PRs and 16 had SD lasting ≥4 cycles (median, 19 weeks, range, 11-55).

Conclusion: MRX34 treatment with dexamethasone premedication demonstrated a manageable toxicity profile in most patients and some clinical activity. Although the trial was closed early due to serious immune-mediated AEs that resulted in four patient deaths, dose-dependent modulation of relevant target genes provides proof-of-concept for miRNA-based cancer therapy.

Clinical Trial Registration: NCT01829971.
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http://dx.doi.org/10.1038/s41416-020-0802-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251107PMC
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

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

Oxaliplatin-Based Adjuvant Chemotherapy for Rectal Cancer After Preoperative Chemoradiotherapy (ADORE): Long-Term Results of a Randomized Controlled Trial.

J Clin Oncol 2019 11 8;37(33):3111-3123. Epub 2019 Oct 8.

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

Purpose: We evaluated the role of oxaliplatin as adjuvant chemotherapy in patients with rectal cancer who received preoperative chemoradiotherapy (CRT) with fluoropyrimidine monotherapy and total mesorectal excision (TME).

Methods: The ADORE trial (adjuvant oxaliplatin in rectal cancer) is a multicenter, randomized trial in patients with postoperative ypStage II (ypT3-4N0) or III (ypTN1-2) rectal cancer after fluoropyrimidine-based preoperative CRT and TME. Patients were randomly assigned (1:1) to receive adjuvant chemotherapy either with FL (fluorouracil 380 mg/m and leucovorin 20 mg/m) or FOLFOX (oxaliplatin 85 mg/m, leucovorin 200 mg/m, and fluorouracil bolus 400 mg/m on day 1, fluorouracil infusion 2,400 mg/m for 46 hours). Stratification factors included ypStage and participating center. Primary end point was disease-free survival (DFS).

Results: A total of 321 patients were enrolled between November 19, 2008, and June 12, 2012. Six-year DFS rates were 68.2% in the FOLFOX arm versus 56.8% in the FL arm, with a stratified hazard ratio of 0.63 (95% CI, 0.43 to 0.93; = .018) by intention-to-treat analysis. In the subgroup analysis for DFS, FOLFOX was favorable versus FL in patients with ypStage III, ypN1b, ypN2, high-grade histology, minimally regressed tumor, and an absence of lymphovascular or perineural invasion. Six-year overall survival rate was 78.1% in the FOLFOX arm versus76.4% in the FL arm (hazard ratio, 0.73; 95% CI, 0.45 to 1.19; = .21). In the subgroup analysis for OS, FOLFOX was favorable versus FL in patients with ypN2 and minimally regressed tumor.

Conclusion: Adjuvant FOLFOX improved DFS in patients with rectal cancer with ypStage II and III disease after preoperative CRT. Adjuvant FOLFOX may be considered on the basis of the postoperative pathologic stage in those who received preoperative CRT and TME.
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http://dx.doi.org/10.1200/JCO.19.00016DOI Listing
November 2019

Targeted next-generation DNA sequencing identifies Notch signaling pathway mutation as a predictor of radiation response.

Int J Radiat Biol 2019 12 26;95(12):1640-1647. Epub 2019 Sep 26.

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

Identifying the association between somatic mutations and the radiation response of tumor is essential for understanding the mechanisms and practicing personalized radiotherapy. The present study aimed to discover specific genes or pathways that are associated with radiation response using targeted next-generation DNA sequencing. Fifty-five patients with various solid tumors whose specimen were sequenced using institutional panel which includes 148 cancer-related genes and received radiotherapy for a measurable tumor were analyzed. Patients with irradiated tumors in complete or partial remission for more than 6 months were defined as responders. Association between mutations including pathogenic single nucleotide variants and insertions/deletions in the 148 genes and 39 molecular pathways and radiation response was investigated. Analyzing 17 responders and 38 non-responders, biologically effective dose (BED), but not concurrent chemotherapy, was associated with radiation response. No single gene correlated with radiation response. Mutations in Notch signaling pathway were associated with radiosensitivity after correction for multiple comparison (adjusted  = .094). When BED and Notch signaling pathway mutation were tested with logistic regression, both variables were associated with radiation response. Our results suggest that somatic mutations in Notch signaling pathway may be related to sensitivity to radiation, although these results should be validated in a larger and more homogeneous cohort.
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http://dx.doi.org/10.1080/09553002.2019.1665212DOI Listing
December 2019

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

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
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