Histopathologic and Molecular Biomarkers of PD-1/PD-L1 Inhibitor Treatment Response among Patients with Microsatellite Instability‒High Colon Cancer

형재원,조은정,김지훈,김좌훈,김정은,홍용상,김태원,성창옥,김선영 대한암학회 2022 Cancer Research and Treatment Vol.54 No.4

Purpose Recent clinical trials have reported response rates < 50% among patients treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for microsatellite instability–high (MSI-H) colorectal cancer (CRC), and factors predicting treatment response have not been fully identified. This study aimed to identify potential biomarkers of PD-1/PD-L1 inhibitor treatment response among patients with MSI-H CRC. Materials and Methods MSI-H CRC patients enrolled in three clinical trials of PD-1/PD-L1 blockade at Asan Medical Center (Seoul, Republic of Korea) were screened and classified into two groups according to treatment response. Their histopathologic features and expression of 730 immune-related genes from the NanoString platform were evaluated, and a machine learning–based classification model was built to predict treatment response among MSI-H CRCs patients. Results A total of 27 patients (15 responders, 12 non-responders) were included. A high degree of lymphocytic/neutrophilic infiltration and an expansile tumor border were associated with treatment response and prolonged progression-free survival (PFS), while mucinous/signet-ring cell carcinoma was associated with a lack of treatment response and short PFS. Gene expression profiles revealed that the interferon-γ response pathway was enriched in the responder group. Of the top eight differentially expressed immune-related genes, PRAME had the highest fold change in the responder group. Higher expression of PRAME was independently associated with better PFS along with histologic subtypes in the multivariate analysis. The classification model using these genes showed good performance for predicting treatment response. Conclusion We identified histologic and immune-related gene expression characteristics associated with treatment response in MSI-H CRC, which may contribute to optimal patient stratification. Purpose Recent clinical trials have reported response rates < 50% among patients treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for microsatellite instability‒high (MSI-H) colorectal cancer (CRC), and factors predicting treatment response have not been fully identified. This study aimed to identify potential biomarkers of PD-1/PD-L1 inhibitor treatment response among patients with MSI-H CRC. Materials and Methods MSI-H CRC patients enrolled in three clinical trials of PD-1/PD-L1 blockade at Asan Medical Center (Seoul, Republic of Korea) were screened and classified into two groups according to treatment response. Their histopathologic features and expression of 730 immune-related genes from the NanoString platform were evaluated, and a machine learning–based classification model was built to predict treatment response among MSI-H CRCs patients.Results A total of 27 patients (15 responders, 12 non-responders) were included. A high degree of lymphocytic/neutrophilic infiltration and an expansile tumor border were associated with treatment response and prolonged progression-free survival (PFS), while mucinous/signet-ring cell carcinoma was associated with a lack of treatment response and short PFS. Gene expression profiles revealed that the interferon-γ response pathway was enriched in the responder group. Of the top eight differentially expressed immune-related genes, <i>PRAME</i> had the highest fold change in the responder group. Higher expression of <i>PRAME</i> was independently associated with better PFS along with histologic subtypes in the multivariate analysis. The classification model using these genes showed good performance for predicting treatment response.Conclusion We identified histologic and immune-related gene expression characteristics associated with treatment response in MSI-H CRC, which may contribute to optimal patient stratification.

GASTric Cancer HER2 Re-Assessment Study 2 (GASTHER2): HER2 Re-assessment for Initially HER2-Negative Advanced Gastric Cancer Patients after Progression on First-Line Treatment

형재원,김형돈,류민희,박영수,문미선,강윤구 대한암학회 2024 Cancer Research and Treatment Vol.56 No.1

Purpose Heterogeneous human epidermal growth factor receptor 2 (HER2) overexpression in gastric cancer may lead to a misdiagnosis of HER2 status. Accurate assessment of HER2 status is essential for optimal treatment as novel HER2-directed agents are being investigated in various clinical settings. We evaluated the usefulness of HER2 re-assessment following progression on first-line treatment in initially HER2-negative advanced gastric cancer (AGC) patients.Materials and Methods We enrolled 177 patients with baseline HER2-negative AGC and performed HER2 re-assessment after progression on first-line treatment from February 2012 to June 2016 at Asan Medical Center, Seoul, Korea. The re-assessed HER2 status was analyzed with baseline HER2 status and clinical characteristics.Results The median age was 54 years (range, 24 to 80 years), and 123 patients (69.5%) were men. Seven patients (4.0%) were HER2-positive on the re-assessment. Patients with baseline HER2 negativity confirmed by a single test (n=100) had a higher HER2-positive re-assessment rate compared to those who had repeated baseline testing (n=77) (5.0% vs. 2.6%). Among the patients with single baseline HER2 testing, the rate was higher in patients with baseline HER2 immunohistochemistry (IHC) 1+ compared to those with IHC 0 (13.4% vs. 3.6%).Conclusion Overall, 4.0% of patients with baseline HER2-negative AGC were HER2-positive on re-assessment, and the HER2-positive re-assessment rate was higher among patients who had a single test at baseline. HER2 re assessment may be considered for initially HER2-negative patients to determine their eligibility for HER2-directed therapy, particularly if their HER2 negativity was determined by a single test, especially if they had a single baseline HER2 IHC 1+ test.

Clinical Outcomes of Small Cell Carcinoma of the Genitourinary Tract and the Prognostic Significance of the Tumor Immune Microenvironment

형재원,김형돈,김기환,조영미,유연미,김상엽,박인근,윤신교,이재련 대한암학회 2024 Cancer Research and Treatment Vol.56 No.2

Purpose Small cell carcinoma of the genitourinary tract (GU SCC) is a rare disease with a poor prognosis. There are only limited treatment options due to insufficient understanding of the disease. In this study, we analyzed the clinical outcomes of patients with GU SCC and their association with the tumor immune phenotype.Materials and Methods Patients diagnosed with GU SCC were included. Survival outcomes according to the primary location (prostate and non-prostate) and stages (limited disease [LD] and extensive disease [ED]) were analyzed. We performed multiplex immunohistochemistry (IHC) in non-prostate SCC patients and analyzed the immune cell population.Results A total of 77 patients were included in this study. Their median age was 71 years, 67 patients (87.0%) were male, and 48 patients (62.3%) had non-prostate SCC. All patients with ED (n=31, 40.3%) received etoposide plus platinum (EP) as initial treatment and median overall survival (OS) was 9.7 months (95% confidence interval [CI], 7.1 to 18.6). Patients with LD (n=46, 59.7%) received EP followed by radiotherapy or surgery, and 24-months OS rate was 63.6% (95% CI, 49.9 to 81.0). The multiplex IHC analysis of 21 patients with non-prostate SCC showed that patients with a higher density of programmed death-ligand 1–expressing CD68+CD206+ M2-like macrophages had significantly worse OS outcomes with an adjusted hazards ratio of 4.17 (95% CI, 1.25 to 14.29; adjusted p=0.02).Conclusion Patients with GU SCC had a poor prognosis, even those with localized disease. The tumor immune phenotypes were significantly associated with survival. This finding provides new insights for treating GU SCC.

Clinical Benefit of Maintenance Therapy for Advanced Biliary Tract Cancer Patients Showing No Progression after First-Line Gemcitabine Plus Cisplatin

형재원,김범준,유창훈,김규표,정재호,장흥문,류백렬 대한암학회 2019 Cancer Research and Treatment Vol.51 No.3

Purpose Gemcitabine plus cisplatin (GemCis) is the standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC). In ABC-02 study, the BTC patients received up to 6-8 cycles of 3-weekly GemCis; however, those without progression often receive more than 6-8 cycles. The clinical benefit of maintenance treatment in patients without progression is uncertain. Materials and Methods Advanced BTC patients treated with GemCis between April 2010 and February 2015 at Asan Medical Center, Seoul, Korea, were retrospectively analysed. The patients without progression after 6-8 cycles were stratified according to further treatment i.e., with or without further cycles of GemCis (maintenance vs. observation groups). The primary endpoint was overall survival (OS) and progression-free survival (PFS). Results Among the 740 BTC patients in the initial screen, 231 cases (31.2%) were eligible for analysis (111 in the observation group, 120 in the maintenance group). The median OS from the GemCis initiation was 20.5 months (95% confidence interval [CI], 15.4 to 25.6) and 22.4 months (95% CI, 17.0 to 27.8) in the observation and maintenance groups, respectively (p=0.162). The median PFS was 10.4 months (95% CI, 7.0 to 13.8) and 13.2 months (95% CI, 11.3 to 15.2), respectively (p=0.320). Conclusion GemCis maintenance is not associated with an improved survival outcome.

주관절에 발생한 상과염의 해부병리학적 소견에 대한 고찰

김유진(Kim Eugene),형재원(Hyung JaeWon),김동훈(Kim DongHoon),한병용(Han Byeong-Ryong) 대한견주관절의학회 2016 대한견주관절학회 학술대회논문집 Vol.2016 No.7

한국인 상완골 근위부의 구조적 분석

유정현(Jeong Hyun Yoo),정수태(Soo Tai Chung),조병채(Byung Chae Jo),형재원(Jae Won Hyung),백두진(Doo Jin Bak) 대한정형외과학회 2013 대한정형외과학회지 Vol.48 No.5

목적: 상완골 근위부의 해부학적 재형성을 위한 다양한 형태의 제3세대 견관절 치환술이 시행되고 있지만 한국인을 대상으로 한 상완골 근위부 구조에 대한 연구는 미미하다. 이에 저자들은 한국인의 상완골 근위부의 구조적 분석 결과에 대해 보고하고자 한다. 대상 및 방법: 2009년 1월부터 2011년 10월까지 명지병원에 내원하여 컴퓨터단층촬영을 시행한 100개의 상완골을 대상으로 하였고, 평균연령은 48세(17-83세)였다. 컴퓨터단층촬영 영상을 토대로 상완골 두 관절면의 직경, 상완골 저고, 상완골 곡률반경, 상완골 경사각, 상완골 두와 대결절 사이 거리, 결절 사이 고랑과 상완골 간부 사이의 각, 상완골 외측부각, 내측 오프셋, 후측 오프셋의 총 9가지 항목을 측정하고, 연령별, 성별로 분류하여 비교 분석하였다. 결과: 상완골 두 관절면의 직경은 42.70±3.57도 (이하 평균수치), 상완골 두 저고는 14.30±2.0 mm, 상완골 두 곡률반경은 22.50±1.97 mm였으며 세 개 항목에 있어 성별로 유의한 차이를 보였다. 상완골 경사각은 130.00±4.28도, 상완골 두와 대결절 사이는 7.50±0.99 mm, 결절 사이 고랑과 상완골 간부 사이의 각은 6.60±0.92도, 상완골 외측부각은 163.40±4.05도, 내측 오프셋은 5.20±2.10 mm, 후측 오프셋은 3.10±1.80 mm를 나타냈다. 결론: 한국인의 상완골 근위부의 해부학적인 구조에 대한 연구 결과가 한국인에 적합한 견관절 치환물을 디자인하는 데 도움이 되고, 임상에 적용하여 보다 정확한 해부학적 재형성이 가능하리라 생각한다. Purpose: Third generation shoulder arthroplasty is widely performed nowadays; however, few studies on the anatomy of the proximal humerus in the Korean population have been reported. The authors have attempted to review the anatomy of the proximal humerus. Materials and Methods: The study sample consisted of 100 humeri of patients with a mean age of 48 years (range of 17 to 83 years) who underwent computed tomography imaging between January 2009 and October 2011 at Myongji Hospital. Diameter of the articular surface, head thickness, radius of curvature, head inclination, head to tuberosity height, bicipital groove-shaft angle, lateral angle, medial offset and posterior offset were analyzed. Results were compared depending on age and gender. Results: Mean values of diameter of the articular surface was 42.70±3.57 mm, head thickness was 14.3±2.0 mm, and radius of curvature was 22.50±1.97 mm; these three variables showed significant sex differences. Head inclination was measured as 130.00±4.28 degrees, head to tuberosity height was 7.50±0.99 mm, bicipital groove-shaft angle was 6.60±0.92 degrees, and lateral angle was 163.40±4.05 degrees. Mean medial and posterior offset were 5.2±2.1 mm and 3.1±1.8 mm, respectively. Conclusion: Based on the results of this study, the measurement values of Korean humeri can be used in design of the arthroplasty prosthesis, and this will lead to more accurate anatomical reconstruction of the shoulder joint.

동시에 발생된 일측성 고관절, 슬관절 및 족부 관절의 외상성 골절 및 탈구 -증례 보고-

김형수 ( Hyoung Soo Kim ),김주학 ( Ju Hak Kim ),박상준 ( Sang Joon Park ),형재원 ( Jae Won Hyung ) 대한골절학회 2012 대한골절학회지 Vol.25 No.1

Although clinical cases of ipsilateral knee and hip joint dislocation have been reported, there are no reports of simultaneous ipsilateral hip, knee, and foot dislocations. We report here a case of a patient who had ipsilateral hip, knee, and foot joint dislocations, and review the relevant literature.

한국인 이두 구의 해부학적 구조의 분석과 상완이두근건 장두의 병변과의 관련성

정수태(Soo-Tai Chung),유정현(Jeong Hyun Yoo),형재원(Jae-Won Hyung),조병채(Byung-Chae Jo) 대한견주관절의학회 2013 대한견주관절학회 학술대회논문집 Vol.2013 No.3

Analysis of Plasma Circulating Tumor DNA in Borderline Resectable Pancreatic Cancer Treated with Neoadjuvant Modified FOLFIRINOX: Clinical Relevance of DNA Damage Repair Gene Alteration Detection

임동훈,윤현석,김규표,류백열,이상수,박도현,송태준,황대욱,이재훈,송기병,김송철,홍승모,형재원,유창훈 대한암학회 2023 Cancer Research and Treatment Vol.55 No.4

Purpose There are no reliable biomarkers to guide treatment for patients with borderline resectable pancreatic cancer (BRPC) in the neoadjuvant setting. We used plasma circulating tumor DNA (ctDNA) sequencing to search biomarkers for patients with BRPC receiving neoadjuvant mFOLFIRINOX in our phase 2 clinical trial (NCT02749136). Materials and Methods Among the 44 patients enrolled in the trial, patients with plasma ctDNA sequencing at baseline or post-operation were included in this analysis. Plasma cell-free DNA isolation and sequencing were performed using the Guardant 360 assay. Detection of genomic alterations, including DNA damage repair (DDR) genes, were examined for correlations with survival. Results Among the 44 patients, 28 patients had ctDNA sequencing data qualified for the analysis and were included in this study. Among the 25 patients with baseline plasma ctDNA data, 10 patients (40%) had alterations of DDR genes detected at baseline, inclu-ding ATM, BRCA1, BRCA2 and MLH1, and showed significantly better progression-free survival than those without such DDR gene alterations detected (median, 26.6 vs. 13.5 months; log-rank p=0.004). Patients with somatic KRAS mutations detected at baseline (n=6) had significantly worse overall survival (median, 8.5 months vs. not applicable; log-rank p=0.003) than those without. Among 13 patients with post-operative plasma ctDNA data, eight patients (61.5%) had detectable somatic alterations. Conclusion Detection of DDR gene mutations from plasma ctDNA at baseline was associated with better survival outcomes of pati-ents with borderline resectable pancreatic ductal adenocarcinoma treated with neoadjuvant mFOLFIRINOX and may be a prognostic biomarker.