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Greco, Venanzio R. "Discussion of “Effects of Strain Localization on Seismic Active Earth Pressures” by Jian-Min Zhang, Fei Song, and De-Ji Li." Journal of Geotechnical and Geoenvironmental Engineering 137, no. 12 (December 2011): 1316. http://dx.doi.org/10.1061/(asce)gt.1943-5606.0000493.
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Zhang, Jian-Min, Fei Song, and De-Ji Li. "Closure to “Effects of Strain Localization on Seismic Active Earth Pressures” by Jian-Min Zhang, Fei Song, and De-Ji Li." Journal of Geotechnical and Geoenvironmental Engineering 137, no. 12 (December 2011): 1316–17. http://dx.doi.org/10.1061/(asce)gt.1943-5606.0000594.
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Kim, Joseph, Jai-Hee Moon, Kyung-Mi Lee, Hyun Ryu, Eun Hye Park, Sang Hee Kim, Jeong Seok Kim, et al. "Abstract 6219: WM-S1, the novel small molecule inhibitor of mutant RTK/receptor tyrosine kinase, for the treatment of cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6219. http://dx.doi.org/10.1158/1538-7445.am2022-6219.
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Abstract As the representative targeted anticancer drug for colon cancer patients, cetuximab is the EGFR targeted therapeutic antibody and used for treatment of KRAS wild type cancers. Even some patient with KRAS wt gene did not respond cetuximab. However, there is no treatment available for cetuximab-resistant patient group, which is almost 50% of KRAS WT gene holders. Recently, our team identified cetuximab primary resistant related proteins named as mtRTK (mutant receptor tyrosine kinase) by array analysis based cetuximab responder or non-responder colon cancer patient tissues. We investigated mtRTK’s oncogenic potential as a novel anti-cancer target. A large proportion of colon cancer patients (36.2% Caucasian, 56.9% Korean) expressed the mtRTK was identified, using the sequencing analysis of patient samples. Based on these results, our efforts have led to the discovery of WM-S1, mtRTK inhibitor, which is the first mtRTK inhibitor in clinical development. The potent enzyme inhibitor showed a high anticancer activity confirmed in Patient-Derived Cells (PDC) and Patient-Derived Xenograft (PDX) animal models expressing the mutation. In preclinical studies demonstrate that WM-S1 is well tolerated in rats and dogs. Furthermore, WM-S1 has potent anticancer activities for various solid tumor (NSCLC, cholangiocarcinoma, etc.) including activated mtKRAS colon cancer expressing the mtRTK. Currently we are investigating WM-S1 in a phase 1a trial in AUS, which is the first mtRTK inhibitor in clinical development. Meanwhile, the mtRTK inhibitor WM-S1 drives antitumor immunity (with anti-PD-L1) in NSCLC. Combinational approaches with immunotherapy showed that synergistic effect of WM-S1 and anti-PD1 monoclonal antibody, suppressing tumor growth by 75% in anti-PD1 resistance NSCLC-derived humanized mouse model. A phase 1b trial is expected to develop WM-S1 through not only indication expansion but also combination therapy with immuno-checkpoint inhibitors in the USA, AUS and KOR from Q2 2022. In conclusion, mtRTK is a potential oncogenic driver mutation in various solid tumor. A first-in-class anticancer agent WM-S1 targeting mtRTK can be promising therapeutic agents for cetuximab-resistant colon cancer patients regardless of KRAS mutation status and other cancers. Citation Format: Joseph Kim, Jai-Hee Moon, Kyung-Mi Lee, Hyun Ryu, Eun Hye Park, Sang Hee Kim, Jeong Seok Kim, Young Ok Ko, Yong Seok Kim, Hyo Jin Kim, Tae Young Kim Kim, Moon Seong Yoo, Soll Jin, Seongrak Kim, Yoon Sun Park, Min Ki Lee, Mi So Lee, Ji Hyun Go, Yu Geun Ji, Jun Hyung Lee, Haneul Lee, Min Hwa Kim, Eun Hee Ko, Yeo Jin Lee, Seung-Mi Kim, Joon-yee Jeong, Yeon-seoung Choi, Seung-geon Bae, Jinwoo Lee, Won Jun Lee, Min-Kyeong Kim, Ji min Shin, Dong-in Koh, Sun-Chul Hur, Chun-Ho Park, Hyun Ho Lee, Dong-Hoon Jin. WM-S1, the novel small molecule inhibitor of mutant RTK/receptor tyrosine kinase, for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6219.
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B., Ariunbaigali. "“Гуулин улсын судар”-ын тухай." Mongolian Journal of Foreign Languages and Culture 20, no. 450 (March 2, 2023): 15–26. http://dx.doi.org/10.22353/mjflc.v20i450.2852.
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History of Goryeo Dynasty is one of the official histories of Korea and included Goryeo Dynasty’s politic, economy, social culture and biography of public figures which is most important fundamental source for our current studying the ancient history of that time. Therefore, many research studies has been made on the History of Goryeo Dynasty in perspective of manuscript study, literature study and culture study in apart from of history, at present in Korea. This source is written right after establishment of Joseon Dynasty as chronicle of the Goryeo Dynasty’s late period, whereas Korean scholars cannot eject view that political justification view point reflected on establishment of Joseon Dynasty.
However, the Goryeo Dynasty’s all time king’s Joseon wangjo sillok (실록. 實錄Veritable Records of the Joseon Dynasty) was used as the main source of creating the History of Goryeo Dynasty and the people present at that time such as “Comprehensive records arranged by year (편년통록. 編年通錄)” by Kim Kwan-ui (김관의. 金寬毅), “Comprehensive records of Gangmo (편년강목. 編年綱目)” by Min Ji (민지. 閔漬), “Records of reflection from Mirror (금경록. 金鏡錄)” by Yi Saek (이색. 李穡)and Yi Yinbok (이인복. 李仁復), “Sikmok pyeonsurok (식목편수록. 拭目編修錄)” and “Prescribed Ritual Text of the Past and Present (고금상정례. 古今詳定禮)” by Choe Yun-ui(최윤의. 崔允儀), “Ikjae-nango(익재난고. 益齋亂藁)” and “Scribbles of Old Man Oak (역옹패설. 櫟翁稗說)” by Yi Jehyeon (이제현. 李齊賢), and “Jugwanyukik (주관육익. 周官六翼)” by Kim, Goo-Yong(김구용. 金九容) are used as reference. Thus, researchers conclude that it describe assure true history of that period and one can say it elevate the value of the source.
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Park, Minsu, Tae-Min Cho, Soeun Park, Jung Min Park, Juyeon Seo, Dongmi Ko, Seongjae Kim, et al. "Abstract 3712: The C-terminal HSP90 inhibitor, a novel deguelin derivative, exerts anti-metastatic effects in triple-negative breast cancer by targeting cancer stem-like properties." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3712. http://dx.doi.org/10.1158/1538-7445.am2022-3712.
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Abstract Purpose: Triple-negative breast cancer (TNBC) still relies on non-selective cytotoxic anticancer agents due to the absence of established molecular targets for the phenotype. The heat shock protein 90 (HSP90) is a promising therapeutic target because it affects the overall progression of cancer, including cell proliferation, angiogenesis and metastasis. A variety of N-terminal HSP90 inhibitors have been tried several times in clinical trials, but none have been approved for clinical use to date due to issues including heat shock response (HSR) induction, undesirable effects, and clinical toxicity. In this study, we sought to investigate whether a novel C-terminal HSP90 inhibitor SL-145 could resolve metastasis in TNBC through inhibition of cancer stem-like properties. Experimental Design: The effects of SL-145 on TNBC cell lines in vitro were evaluated in terms of cell proliferation, apoptosis, caspase-3 activity, breast cancer stem cell (BCSC)-like properties and heat shock response. An orthotopic allograft model with 4T1 mammospheres was used to examine the effect of SL-145 on tumor growth and metastasis in vivo. Results: SL-145 induces apoptosis without triggering the HSR and simultaneously inhibits several oncogenic signaling pathways including AKT, MEK/ERK and JAK2/STAT3. SL-145 effectively targets BCSC-like properties with significant reductions in CD44, CD49f and ALDH1 expression as well as impairment of mammosphere-forming ability. To confirm the physiological relevance of our in vitro observations, we investigated the effects of SL-145 on tumor growth, angiogenesis and metastasis in mammosphere-derived allograft tumors with self-renewal capacity. SL-145 administration reduced tumor burden and angiogenesis, which were enriched in BCSCs, and it resulted in significant reductions in lung and liver metastases. In addition, no toxic effects of inhibitors on markers of liver or renal function were observed. Conclusion: Our findings suggest that SL-145 may represent an effective therapeutic approach for targeting cancer stem cells and simultaneous inhibition of the HSP90 client oncoprotein to treat TNBC with a heterogeneous and aggressive nature. Citation Format: Minsu Park, Tae-Min Cho, Soeun Park, Jung Min Park, Juyeon Seo, Dongmi Ko, Seongjae Kim, So Ra Seuk, Yong Gu Kang, Kee Dal Nam, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo. The C-terminal HSP90 inhibitor, a novel deguelin derivative, exerts anti-metastatic effects in triple-negative breast cancer by targeting cancer stem-like properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3712.
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Hoang, Tung, Min Jung Kim, Ji Won Park, Seung-Yong Jeong, Jeeyoo Lee, and Aesun Shin. "Abstract 3062: Modifiable factors and gut microbiome alteration among colorectal cancer patients." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3062. http://dx.doi.org/10.1158/1538-7445.am2022-3062.
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Abstract Background: Previous study have indicated an association of microbial dysbiosis with stages of colorectal cancer (CRC). Meanwhile, higher microbial stochasticity has been introduced as the Anna Karenina principle (AKP) effect, which originates from the opening line of Leo Tolstoy and is translated in the microbiome as “all healthy microbiomes are similar; each dysbiotic microbiome is dysbiotic in its own way”. Here, we aim to elucidate the effect of modifiable factors on microbiome stochasticity related to dysbiosis in CRC. Methods: Fecal samples from 331 CRC patients, were collected prior to their surgery at Seoul National University Hospital. Bacteria that were enriched in early- and late-stage CRC groups were identified by linear discrimination analysis effect size (LEfSE) method, which was then used to calculate microbial dysbiosis index (MDI). The association of dietary choices with microbiome variability was addressed using the LEfSE analysis. The difference of intra-sample similarity index among lifestyle factors and metabolic diseases was tested to examine the AKP effect. A tree-based analysis of food choices was constructed. We then applied Procrustes framework to analyze the shape of dietary diversity and microbiome. Results: The LEfSE identified Leuconostoc, Oxalobacter, Acidaminococcus, and Methanobrevibacter were enriched in early-stage CRC, whereas Bacteroides, Fusobacterium, Lachnoanaerobaculum, Clostridium, and Granulicatella were enriched in late-stage CRC patients. The MDI derived from these bacteria had 64.2% predictive ability for CRC stages, with sensitivity and specificity of 61% and 69%, respectively. The AKP effect was found for history of smoking, alcohol consumption, and diabetes, whereas obesity and hypertension showed anti-AKP effect. For dietary choices, the hierarchical tree of foods and nutrients did not shape the microbial between-sample diversity. Additionally, high MDI was related with a high intake of pizza/hamburger, poultry, and light-vegetable combination. Conclusion: Our study contributed to current evidence of the microbiome structure and dysbiosis at different stages of CRC. Furthermore, history of smoking, alcohol consumption, and diabetes showed AKP effect in CRC patients. Non-significant association between dietary choices and microbiome diversity supported a small variation of microbiome profiles explained by dietary intake at the population level. Citation Format: Tung Hoang, Min Jung Kim, Ji Won Park, Seung-Yong Jeong, Jeeyoo Lee, Aesun Shin. Modifiable factors and gut microbiome alteration among colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3062.
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Ryu, Won-Ji, Shinyoung Park, Jeong Dong Lee, Yumi Hwang, Seongyeon Jo, Kweon Tae Yong, Ja Seung Koo, Min Hwan Kim, Joo Hyuk Sohn, and Hyung Seok Park. "Abstract 178: Establishment of patient-derived organoid of breast cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 178. http://dx.doi.org/10.1158/1538-7445.am2023-178.
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Abstract A patient-derived organoid (PDO) is an in vitro three-dimensional model which shows similar features in phenotypic and genetic aspects with primary tissue from patients. PDOs are useful for preclinical studies including drug sensitivity tests of tumors from individual patients as well as development of novel targeted agents. Collectively, PDOs are recently introduced as an emerging platform for personalized medicine. We obtained a total of 100 surgical specimens from 100 patients with breast cancer at the Yonsei Cancer Center, Severance Hospital, Seoul, Korea. One of the tissue specimens was acquired from a breast cancer patient-derived xenograft model. We dissociated the tissues and isolated breast cancer primary tumor cells from the samples, and then the cells were cultured in basement membrane-like matrix in 3D manner with growth medium with supplements. We defined successful establishment of PDOs as continuous growth after 3 passaging. Among all 100 cases, 32 cases failed to culture or passage, however, 41 cases were successfully cultured over 3 passages. In addition, the remaining 27 cases are still in progress of establishment. Success rate of PDO was 68% (68/100). Subtypes of primary tumors of the PDO were 33.8% (23/68) of luminal A, 26.5% (18/68) of luminal B, 26.5% (18/68) of triple-negative, 5.9% (4/68) of triple-positive and 7.4% (5/68) of HER2-enriched. Success rates of each subtype were 69.7% (23/33) of luminal A, 72.0% (18/25) of luminal B, 66.7% (18/27) of triple-negative, 66.7% (4/6) of triple-positive and 55.6% (5/9) of HER2-enriched. Pathologic evaluation using immunohistochemistry revealed that PDOs showed similar morphologic and immunohistochemical features with primary tumors. The selective sensitivity of PARP inhibitor, olaparib, was confirmed in PDOs harboring mutant BRCA1/2 compared with BRCA1/2 wild-type PDOs. Overall, PDOs can be used as a real-time platform for drug sensitivity and screening analyses, and a robust tool for preclinical studies in breast cancer. Citation Format: Won-Ji Ryu, Shinyoung Park, Jeong Dong Lee, Yumi Hwang, Seongyeon Jo, Kweon Tae Yong, Ja Seung Koo, Min Hwan Kim, Joo Hyuk Sohn, Hyung Seok Park. Establishment of patient-derived organoid of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 178.
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Jung, Eunsun, Seojin Jang, Daeil Sung, Soeun Park, Minsu Park, Dongmi Ko, Seongjae Kim, et al. "Abstract 4911: A novel C-terminal of HSP90 inhibitor NCT-547 eliminates cancer stem-like subpopulation in triple-negative breast cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4911. http://dx.doi.org/10.1158/1538-7445.am2023-4911.
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Abstract Triple-negative breast cancer (TNBC) harbors a higher cancer stem cell (CSC)-like population and exhibits a more aggressive metastatic phenotype. Due to the limitations of currently available targeted therapies, there remains a significant unmet need for the development of new targeted therapies for TNBC. Molecular chaperone heat shock protein 90 (HSP90) is attracting attention as an ideal therapeutic target due to it regulates essential biological functions such as cell proliferation, angiogenesis and metastasis. Although N-terminal HSP90 inhibitors have had little clinical success to date, C-terminal HSP90 inhibitors have received relatively little attention. We sought to investigate the effects of a new rationally designed NCT-547 on apoptosis, breast cancer stem cell (BCSC)-like properties, migration ability and heat shock response (HSR) in vitro and tumor growth and metastasis in CSC-enriched allograft model in vivo. NCT-547 inhibits TNBC cell proliferation by simultaneously inactivating several survival factors including AKT, MEK, and STAT3. In addition, NCT-547 effectively targets BCSC-like properties with impairment of ALDH1 activity, CD44+/CD24- phenotype, and 3D mammosphere-forming ability. The expression of HSF-1 target genes such as Hsp90, Hsp70, Hsp27, Hsp40 and Hsp65 is highly overexpressed in TNBC patients. The mRNA abundances of target genes were significantly decreased after NCT-547 challenge. NCT-547 effectively targets both the proliferating TNBC tumor cells and CSCs, markedly reducing tumor growth, coinciding with decreased Ki-67 proliferation index and enhanced apoptosis. Anti-tumor effect of NCT-457 was independent of heat shock response as evidenced by significant downregulation of HSF1 phosphorylation and expression of downstream targets HSPs members. It is noteworthy that NCT-547 did not affect markers of hepatic and renal acute toxicity and was not cytotoxic in non-malignant cells. NCT-547 may therefore have potential to address current limitations in the treatment of TNBC. Citation Format: Eunsun Jung, Seojin Jang, Daeil Sung, Soeun Park, Minsu Park, Dongmi Ko, Seongjae Kim, Juyeon Seo, Kee Dal Nam, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo, Yong koo Kang, So Ra Seock, Jung Min Park. A novel C-terminal of HSP90 inhibitor NCT-547 eliminates cancer stem-like subpopulation in triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4911.
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Jun, So Yon, Sooyoung Cho, Min Jung Kim, Ji Won Park, Seung Yong Jeong, and Aesun Shin. "Abstract 7319: Glycemic traits and colorectal cancer survival in a cohort of South Korean patients: A Mendelian randomization analysis." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7319. http://dx.doi.org/10.1158/1538-7445.am2024-7319.
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Abstract Background: Clinical diabetic traits have been reported to be associated with increased colorectal cancer risk (CRC) in observational studies. Using the Mendelian randomization (MR) analysis method, we examined the causal association between glycemic traits, such as fasting glucose (FG), fasting insulin (FI), and glycosylated hemoglobin A1c (HbA1c), and survival in a cohort of CRC patients. Methods: We conducted a two-sample MR analysis among a cohort of patients with locally advanced CRC at Seoul National University Hospital. Single-nucleotide polymorphisms robustly associated (P<5 × 10−8) with the three glycemic traits were obtained from the Meta-Analyses of Glucose and Insulin-related traits Consortium, Asian Genetic Epidemiology Network, and Korea Biobank Array. Three-year and five-year overall survival (OS) and progression-free survival (PFS) were used as outcomes. Survival analysis was conducted using subgroup analysis by cancer stage and subsite in a multivariate Cox proportional hazards model adjusted for age and sex to examine whether glycemic traits affected survival. Results: A total of 509 patients were included in our final analysis. MR analysis showed that HbA1c levels were associated with poor three-year OS (β=4.20, P=0.02). Sensitivity analyses did not show evidence of any violations of the MR assumptions. In the cancer subgroup analysis of the Cox proportional hazards model, pooled hazard ratios for FG were significantly associated with poor three-year OS and PFS regardless of cancer stage. FI was not significantly associated with any three-year survival endpoints. Among stage III patients, three glycemic traits were significantly associated with both five-year OS and PFS. Location-specific subgroup analysis showed a significant association between three glycemic traits and five-year PFS in patients with left-sided colon cancer. FG was associated with poor three-year survival for colon cancer but not rectal cancer. Conclusions: Our results suggest that FG and HbA1c could be used to predict prognosis in CRC patients. Lifestyle and/or pharmacological interventions targeting glycemic traits could help improve survival for CRC patients. Citation Format: So Yon Jun, Sooyoung Cho, Min Jung Kim, Ji Won Park, Seung Yong Jeong, Aesun Shin. Glycemic traits and colorectal cancer survival in a cohort of South Korean patients: A Mendelian randomization analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7319.
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Lee, Han-Byoel, Ji Gwang Jung, Jung Min Chang, Ji Hyun Chang, Woo Kyung Moon, Kyung Hwan Shin, Il Yong Chung, et al. "Abstract OT1-04-02: The NAUTILUS trial (No Axillary sUrgical Treatment In clinically Lymph node negative patients after UltraSonography): A prospective multicenter randomized phase III trial (NCT04303715)." Cancer Research 82, no. 4_Supplement (February 15, 2022): OT1–04–02—OT1–04–02. http://dx.doi.org/10.1158/1538-7445.sabcs21-ot1-04-02.
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Abstract Background. Sentinel lymph node biopsy (SLNB) is currently the standard axillary staging procedure for clinically node-negative breast cancer. According to the ACOSOG Z0011 trial, axillary lymph node dissection (ALND) is now often omitted for clinically node-negative cT1-2 breast cancer patients undergoing breast-conserving surgery even if 1 or 2 metastatic lymph nodes (LN) are identified. It was shown that radiotherapy contributes to regional control of the axilla non-inferior to ALND even in the presence of metastatic LNs. Furthermore, LN metastasis has a limited role in planning adjuvant systemic therapy for hormone receptor-negative breast cancers, and also for hormone receptor-positive, HER2-negative breast cancer with increased use of genomic assays. SLNB is not without complications and omitting axillary staging operation could improve quality of life. Trial Design. In this multicenter, phase III randomized controlled trial including 9 study sites in South Korea, we plan to 1:1 randomize 1734 patients to either omit SLNB (Arm 1) or receive SLNB (Arm 2). Additional ALND can be performed according to the discretion of the surgeon according to the SLNB results. All patients must receive whole-breast irradiation ± tumor bed boost. The recommended upper margin of the radiation field is within 2cm of the humeral head. ClinicalTrials.gov identifier: NCT04303715. Eligibility. Inclusion criteria: women ≥19 years; cT1-2N0M0 unilateral invasive breast carcinoma; all molecular subtypes; clinically and radiologically tumor size ≤ 5cm; clinically- and ultrasonogram-negative axillary lymph nodes, or no tumor on core needle biopsy or fine needle aspiration cytology in case of suspicious lymph nodes; candidate for breast-conserving surgery with no restriction to radiotherapy and adequate systemic therapy. Exclusion criteria: history of any malignancy within 5 years (exception: thyroid cancer and well-treated skin cancer except melanoma); bilateral breast cancer; neoadjuvant chemotherapy; candidate for total mastectomy; male breast cancer. Specific Aims. Primary objective is to test the hypothesis that omitting SLNB for breast cancer is non-inferior to axillary staging operation in terms of 5-year disease-free survival. Secondary objectives are to compare overall survival, distant metastasis-free survival, locoregional recurrence, quality of life assessment, and DFS and axillary recurrence according to molecular subtypes. Statistical Methods. With an expected 5-year DFS of 86% for Arm 2, Arm 1(SLNB omission) will be assessed with a non-inferiority limit of 5% and hazard ratio of 1.4, power 80%, and significance level of 5%, where 224 events are required. The calculated sample size is 780 per study arm, resulting in a total of 1,734 patients assuming a 10% drop-out rate. Present Accrual and Target Accrual. The first patient was randomized on September 15, 2020. As of July 9, 2021, 480 patients have been randomized. Target accrual of 1734 patients is expected to be complete by April 2023, with the primary endpoint analysis expected in 2028. Citation Format: Han-Byoel Lee, Ji Gwang Jung, Jung Min Chang, Ji Hyun Chang, Woo Kyung Moon, Kyung Hwan Shin, Il Yong Chung, Seok Jin Nam, Eun-Kyu Kim, Seeyoun Lee, Seho Park, Woo Sung Lim, Yongsik Jung, Wonshik Han. The NAUTILUS trial (No Axillary sUrgical Treatment In clinically Lymph node negative patients after UltraSonography): A prospective multicenter randomized phase III trial (NCT04303715) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-04-02.
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Kan, Zhengyan, Seock-Ah Im, Kyunghee Park, Ji Wen, Kyung-Hun Lee, Yoon-La Choi, Won-Chul Lee, et al. "Abstract PD2-08: Serial genomic profiling reveals molecular mechanisms of breast cancer resistance to palbociclib." Cancer Research 82, no. 4_Supplement (February 15, 2022): PD2–08—PD2–08. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd2-08.
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Abstract CDK4/6 inhibitors such as palbociclib in combination with endocrine therapy (ET) have remarkablyimproved the outcome of patients with ER+/HER2- metastatic breast cancer (MBC). However, manypatients are intrinsically resistant to CDK4/6i therapy, and those who respond eventually acquireresistance. Although high baseline CCNE1 expression and rare alterations in RB1 and FAT1 geneshave been shown to be associated with CDK4/6i resistance, the molecular mechanisms of CDK4/6iresistance are complex and remain poorly understood. To better understand and overcome CDK4/6iresistance, we performed multi-omics profiling of paired tumor biopsies from ER+/HER2- MBCpatients treated with palbociclib combined with ET. Tumor biopsies taken at pre-treatment, on-treatment, and progressive disease (PD) from 71 patients were profiled using whole-exomesequencing (WES), whole-transcriptome sequencing (RNA-Seq) and IHC analysis. Ourcomprehensive analysis identified several tumor intrinsic molecular markers associated with worsePFS, including the Luminal B subtype (p=0.012, HR=2.593), BRCA1/2 pathogenic mutation (p=0.012,HR=2.67) and mutation signatures linked to APOBEC enzymatic activity (p=0.002, HR=3.19).Conversely, the estrogen response signature (p=0.006, HR=0.43) was associated with favorableprognosis. Unsupervised analysis revealed a cluster of tumors enriched in homologousrecombination deficiency (HRD) linked genomic scars that was associated with poor prognosis(p=0.005, HR=2.49). Of note, these HRD-high tumors responded even more poorly to treatment whenco-occurring with TP53 somatic mutations. Integrative analysis further identified three poorprognosis clusters (IC2-4) enriched in Luminal B, proliferative and HRD features when compared tothe favorable prognosis cluster (IC1).Comparing baseline vs. PD samples, we observed a pattern of post-treatment enrichment for the poorprognosis markers. In addition, breast cancer-associated genes such as BRCA1/2, TP53 and PTENharbored a higher prevalence of genomic alterations including somatic mutation, amplification,. deletion and gene fusion at PD. Cell cycle gene expression and signatures also markedly increased atPD compared to baseline whereas estrogen response signatures decreased. Upon diseaseprogression, tumors had frequently switched to molecular subtypes with aggressive and estrogenindependent characteristics, demonstrating high plasticity in response to CDK4/6i and ET treatment.These patterns of acquired resistance were validated by IHC analysis of cyclins E1 and E2, Ki67 andpRb. To investigate the genomic alterations responsible for acquired resistance, we compared 21paired baseline and PD samples. We observed that PD-specific RB1 loss-of-function events occurredwith higher prevalence than previously reported, underscoring a major role of cell cycle de-regulation in conferring resistance to CDK4/6 inhibition. In this prospective longitudinal multi-omicsstudy, we identified novel candidate biomarkers that can be used to improve prediction of responseto CDK4/6i. In addition, we derived new insights into the molecular mechanisms of drug resistanceto palbociclib plus ET that will help guide therapeutic strategies and drug development inHR+/HER2− MBC. Citation Format: Zhengyan Kan, Seock-Ah Im, Kyunghee Park, Ji Wen, Kyung-Hun Lee, Yoon-La Choi, Won-Chul Lee, Ahrum Min, Vinicius Bonato, Seri Park, Sripad Ram, Dae-Won Lee, Ji-Yeon Kim, Su Kyeong Lee, Won-Woo Lee, Jisook Lee, Miso Kim, Scott L. Weinrich, Han Suk Ryu, Tae Yong Kim, Stephen Dann, Diane Fernandez, Jiwon Koh, Song Yi Park, Shibing Deng, Eric Powell, Rupesh Kanchi Ravi, Jadwiga Bienkowska, Paul A. Rejto, Woong-Yang Park, Yeon Hee Park. Serial genomic profiling reveals molecular mechanisms of breast cancer resistance to palbociclib [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD2-08.
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Cheng, Minyi, Liulu Zhang, Yuanqi Chen, Xiaosheng Zhuang, Ciqiu Yang, Fei Ji, Hongfei Gao, Mei Yang, Teng Zhu, and Jieqing Li. "Abstract P1-01-03: Feasibility and diagnostic performance of ultrasound assisted carbon nanoparticle suspension versus dual-tracer-guided sentinel lymph node mapping in patients with early breast cancer: A prospective, randomized controlled, phase III clinical trial." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–01–03—P1–01–03. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-01-03.
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Abstract Introduction Our previous research has confirmed that a carbon nanoparticle suspension (CNS) tracer for sentinel lymph node biopsy (SLNB) has a satisfactory identification rate. The aim of this randomized study was to compare the performance of ultrasound-assisted carbon nanoparticle suspension with that of a dual-tracer method using CNS plus indocyanine green (ICG) for sentinel lymph node (SLN) mapping in patients with early breast cancer (BC). Methods This was a prospective, randomized, controlled phase III clinical study. We included patients with primary lymph node-negative (cN0) BC or with initial cN1 BC that downstaged to cN0 after neoadjuvant chemotherapy (NAC). SLNB was performed in all enrolled patients by certified breast surgeons who were well trained in SLNB. The dual method using the CNS and ICG was standardized for SLNB in our study. All patients were randomized 1:1 to receive the CNS assisted by preoperative ultrasound positioning (CNS group) or the CNS plus ICG (CG group) for SLN mapping. The node to which black-stained or fluorescent lymph vessels flowed first was defined as the first sentinel lymph node. If there were other fluorescent or black-stained lymph nodes, they were removed as the second and later SLNs. Resected LNs that contained fluorescent ICG and/or black staining were defined as true sentinel lymph nodes. The remaining palpable and axillary enlarged LNs (not blue stained or without fluorescence) were removed as suspicious SLNs.The primary end point was the SLN identification rate in the CNS group compared with that in the CG group. Secondary end points, including the metastatic SLN rate, SLN counts, metastatic SLN counts, time to the first SLN and adverse events, were compared between the two groups. Results Overall, 340 patients were enrolled and randomized 1:1 to the CNS group and the CNS+ICG group between December 2019 and April 2021. There were 330 evaluable patients, 163 in the CNS group and 167 in the CG group; 10 patients were excluded from the analysis due to incomplete data. Parameters such as average age, tumor stage, and molecular type were comparable between the two groups.The SLN identification rate was 94.5% (154/163) in the CNS group and 95.8% (160/167) in the CG group (P=0.57). The rate of metastatic SLNs in the CNS group was identical to that in the CG group (30.7% vs. 25.1%, P =0.26). No significant differences were observed between the CNS and CG groups in SLN counts (4.6±2.25 vs. 5.07±2.43, P > 0.05), positive metastatic SLN counts (0.53±1.27 vs. 0.43±1.09, P > 0.05), and time to the first SLN (7.75 min±3.08 min vs. 7.60 min±3.29 min, P > 0.05).In the NAC subgroups, the SLN identification rate was 88.9% (32/36) in the CNS group and 90.7% (39/43) in the CG group (P=0.54). The rate of metastatic SLNs in the CNS group was identical to that in the CG group (52.8% vs. 23.3%, P =0.06). No significant differences were observed between the CNS and CG groups in SLN counts (4.67±2.17 vs. 5.62±3.13, P =0.24), positive metastatic SLN counts (0.97±1.38 vs. 0.38±1.09, P > 0.05), and time to the first SLN (7.64 min±3.15 min vs. 7.93 min±4.01 min, P > 0.05). The proportion of patients with cN1 BC was 77.8% (28/36) in the CNS group and 58.1% (25/43) in the CG group. The SLN identification rate was 85.7% (24/28) in the CNS group and 84.0% (21/25) in the CG group for patients with cN1 BC after NAC (P=0.58). The SLN identification rate was 100% in both groups for cN0 patients after NAC.During and after the operation, no complications, including allergic reactions or skin necrosis, occurred in either group. Conclusions The ultrasound-assisted CNS was comparable to the ICG plus CNS technique for SLN mapping in patients with early breast cancer and also has potential application value in SLNB after NAC. Citation Format: Minyi Cheng, Liulu Zhang, Yuanqi Chen, Xiaosheng Zhuang, Ciqiu Yang, Fei Ji, Hongfei Gao, Mei Yang, Teng Zhu, Jieqing Li. Feasibility and diagnostic performance of ultrasound assisted carbon nanoparticle suspension versus dual-tracer-guided sentinel lymph node mapping in patients with early breast cancer: A prospective, randomized controlled, phase III clinical trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-01-03.
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Lee, Eun Ji, Juwon Ahn, You Won Lee, Minyeop Kim, Seung Yeon Oh, Yong Joon Park, Su-Jin Choi, et al. "Abstract 6868: Exploring myeloid landscapes according to EGFR mutated NSCLC tumor microenvironment." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6868. http://dx.doi.org/10.1158/1538-7445.am2024-6868.
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Abstract Introduction: Although the use of immune checkpoint inhibitors (ICIs) has improved the survival rate of some patients, EGFR mutant (MT) NSCLC patients exhibit a poor response to ICIs compared to EGFR wild-type (WT) patients. It has been demonstrated that EGFR MT NSCLC cells contribute to immunosuppressive tumor microenvironments (TMEs) by secreting inhibitory cytokines and metabolites and recruiting pro-tumor immunogenic cells, thereby diminishing ICI efficacy. In particular, myeloid cells represent a major component of the TME and are involved in regulating tumor progression and metastasis, indicating anti- and pro-inflammatory heterogeneous functions. While single-cell based analyses have been conducted in various cell types, studies on the diversity of myeloid cells between EGFR WT and EGFR MT NSCLCs are insufficient. Therefore, we explored to reveal the presence of multifaceted myeloid cell populations and to modulate its functions to augment ICI response in NSCLC patients with EGFR MT using single-cell RNA analysis. Methods: Using the 10x Genomics Chromium system, we have generated single-cell RNA expression of a total of 904,174 cells from primary lung tissues of 95 patients with EGFR-WT (n=35), EGFR-MT TKI naïve (n=55), TKI post (n=5) and matched normal (n=22). Nine distinct cell lineages were annotated with canonical marker gene expression, focusing particularly on the myeloid (n=212,673 cells). Results: We characterized 22 transcriptional states of myeloid cells: 4 clusters of alveolar macrophages (AMs; PPARG+), 4 clusters of interstitial macrophages (IMs; SPP1+, FOLR2+, CCL2+), 4 clusters of conventional DCs (cDCs; CLEC9A+, CD1C+, LAMP3+), 2 clusters of mast cells (KIT+), 1 cluster of plasmacytoid DCs (pDCs; LILRA4+), proliferating cells (MKI67+), monocytes (FCN1+), neutrophil like cells (CSF3R+) and 4 other unidentified clusters. In tumor tissues, IMs constituted a significantly higher proportion compared to normal tissues (p<0.001), with EGFR-WT and EGFR-MT IMs exhibiting distinct characteristics. EGFR-WT IMs had a high proportion of cluster expressing FOLR2, a marker of tissue resident macrophages associated with CD8 T cell infiltration and activation. On the other hand, a major component of IMs from EGFR-MT was a cluster expressing SPP1 and its regulator MIF. SPP1 is well known to be involved in cancer cell progression, epithelial-mesenchymal transition, autophagy, and epigenetic alterations. The abundance of SPP1 IMs in the EGFR-MT TME refers to the formation of an immunosuppressive TME, potentially compromising the effectiveness of ICIs. Conclusions: We found that EGFR-MT TME comprised a high proportion of immunosuppressive IM cluster expressing SPP1, implying that it contributes to an immunosuppressive TME. Our findings suggest the possibility of developing strategies to enhance ICI responses by targeting SPP1-induced immunosuppressive TME in EGFR-mutant NSCLC patients. Citation Format: Eun Ji Lee, Juwon Ahn, You Won Lee, Minyeop Kim, Seung Yeon Oh, Yong Joon Park, Su-Jin Choi, JuHyeon Lee, Kyumin Lim, Kyoung-Ho Pyo, Jae Hwan Kim, Jii Bum Lee, Min Hee Hong, Sun Min Lim, Mi Ran Yun, Byoung Chul Cho. Exploring myeloid landscapes according to EGFR mutated NSCLC tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6868.
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Zhang, Jian, Dongmei Ji, Li Cai, Herui Yao, Min Yan, Xiaojia Wang, Weina Shen, et al. "Abstract P2-13-10: First-in-human HER2-targeted bispecific antibody KN026 for the treatment of patients with HER2-positive metastatic breast cancer: Results from a phase I study." Cancer Research 82, no. 4_Supplement (February 15, 2022): P2–13–10—P2–13–10. http://dx.doi.org/10.1158/1538-7445.sabcs21-p2-13-10.
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Abstract PURPOSE KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. This firstinhuman Phase I study evaluated the safety/tolerability, pharmacokinetics (PK), preliminary efficacy, and potential predictive biomarker activity of KN026 administered as monotherapy to HER2-positive metastatic breast cancer (MBC) patients. METHODS Female patients with HER2 positive MBC who failed prior antiHER2 therapies received intravenous KN026 monotherapy at 5 mg/kg (QW), 10 mg/kg (QW), 20 mg/kg (Q2W), or 30 mg/kg (Q3W). Dose escalation was guided by a “3+3” doseescalation rule followed by dose expansion. The primary endpoint of the study was to assess safety and ascertain the recommended phase 2 dose (RP2D). RESULTS 63 patients were enrolled with a median of 3 prior lines of systemic therapies and 2 prior lines of HER2 targeted therapies. Treatment was well tolerated with no DLTs observed. The most common treatment related adverse events (TRAEs) were pyrexia (23.8%), diarrhea (22.2%), aspartate aminotransferase increased (22.2%), alanine aminotransferase increased (22.2%). 4 patients reported Grade 3 TRAEs. Pharmacokinetic analysis indicated that KN026 exposure was dose-dependent, with a terminal elimination halflife of 146 to 282 hours after multiple doses. Results from exposure-response analysis supported the selection of the RP2Ds at 20 mg/kg Q2W or 30 mg/kg Q3W, which had corresponding objective response rates (ORRs) of 32.1% and 24.1%, disease control rates of 60.7% and 82.8%, and median progression-free survival (PFS) of 5.5 and 7.4 months, respectively. Anti-drug antibodies (ADAs) were detected in 3.2% (2/63) of patients at the end of treatment. Cell line data showed that coamplification of HER2 and CDK12 were related to the efficacy of KN026. Translational research in 20 HER2-amplified patients further confirmed that co-amplification (vs. no coamplification) of CDK12 was a promising biomarker in predicting better response to KN026 (ORR of 50% vs. 0% and PFS of 8.2 vs. 2.7 months, P = 0.05 and 0.04, respectively). CONCLUSION KN026, a HER2 bispecific antibody, is well tolerated, with a favorable safety profile and promising anti-tumor activity in the context of its class in patients with HER2-positive breast cancer. Co-amplification of HER2/CDK12 may define patients who benefit more from KN026. Citation Format: Jian Zhang, Dongmei Ji, Li Cai, Herui Yao, Min Yan, Xiaojia Wang, Weina Shen, Yiqun Du, Hui Pang, Xiuping Lai, Huiai Zeng, Jian Huang, Yan Sun, Xinxin Peng, Junfang Xu, Jing Yang, Fei Yang, Ting Xu, Xichun Hu. First-in-human HER2-targeted bispecific antibody KN026 for the treatment of patients with HER2-positive metastatic breast cancer: Results from a phase I study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-10.
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Shin, Rumi, Byunho Jo, Inyeop Jang, Cheong-Il Shin, Jin Sun Choi, Seung-Yong Jeong, Seung Chul Heo, Ji Won Park, Min Jung Kim, and Tae Hyun Hwang. "Abstract 5374: Why only focus on the tumor?: The crucial role of the extra-tumor environment to predict poor responders for locally advanced rectal cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5374. http://dx.doi.org/10.1158/1538-7445.am2023-5374.
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Abstract Introduction As total neoadjuvant therapy for locally advanced rectal cancer (LARC) emerged, the possibility of skipping radiotherapy for poorly responsive patients arose. Machine-learning algorithms have focused on the radiopathologic features of tumor segmentation in order to predict responsiveness to radiotherapy. However, in addition to the tumor itself, there are several factors related to responsiveness, such as vasculature affecting hypoxia or MRI-detected extramural vascular invasion status. We aimed to predict poor responders using pretreatment rectal MRI images without segmentation and to identify which factors mainly contribute to the prediction algorithm. Methods Between Jan 1, 2000, and Dec 30, 2020, 689 consecutive patients were retrospectively included in two hospitals. Poor responders were defined by tumor regression grades (TRG) 2 and 3 that were determined through surgical resection. The ResNet-50 model was trained to predict poor responders from pretreatment rectal MRIs (T2-weighted axial, sagittal, and coronal images). We adopted a tenfold cross-validation for training and testing the model and used Gradient-weighted Class Activation Mapping (Grad-CAM) to highlight the important regions in the MRI scans that help predict poor responders. Results The number in each group of TRG was 108 (15.7%), 250 (36.3%), 265 (38.5%), and 66 (9.6%) for TRG0, TRG1, TRG2, and TRG3, respectively. There were 618 patients in the training cohort and 71 patients in the validation cohort. In the training and validation cohort, the accuracy for the prediction of poor responders was 85.6% (area under the curve (AUC) 0.856 [95% CI 0.761-0.950]) and 70.2% (AUC 0.703 [0.682-0.724]), although without segmentation. Our prediction model achieved a sensitivity of 0.724 (95% CI 0.700-0.748), a specificity of 0.684 (0.658-0.710), a positive predictive value of 0.697 (0.656-0.737), and a negative predictive value of 0.708 (0.666-0.751) in the validation cohort. Grad-CAM showed that the most important part of the accurately predicted images to contribute to the prediction was not the tumor (7/355, 1.9%) but the pelvic vasculature (353/355, 99.4%), including iliac vessels, femoral vessels, and presacral plexus, and followed by the mesorectum (38/355, 10.7%). Conclusion The pelvic vasculature contributes more to predicting poor responders to radiotherapy than the tumor itself. Therefore, when creating a prediction model for responsiveness to radiotherapy in LARC, this should be considered. Citation Format: Rumi Shin, Byunho Jo, Inyeop Jang, Cheong-Il Shin, Jin Sun Choi, Seung-Yong Jeong, Seung Chul Heo, Ji Won Park, Min Jung Kim, Tae Hyun Hwang. Why only focus on the tumor?: The crucial role of the extra-tumor environment to predict poor responders for locally advanced rectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5374.
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Yun, Dabin, Nan Song, Jin-Ah Sim, Min Jung Kim, Ji Won Park, Seung Yong Jeong, and Aesun Shin. "Abstract 5234: Novel predictive biomarker SNPs and polygenic risk scores of immune-related genes for colorectal cancer survival in Korea." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5234. http://dx.doi.org/10.1158/1538-7445.am2023-5234.
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Abstract Background: One of the major topics about colorectal cancer (CRC) is the core role of various immune cells against cancer cells. To comprehensively understand genetic basis of immune system underlying CRC progression, association of single-nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS) of immune-related genes were investigated with colorectal cancer survival. Methods: CRC patients enrolled in the Seoul National University Hospital with prospective follow-up were included in the study. From blood-derived DNA from CRC patients, genome-wide SNPs were genotyped by using the Korea Biobank Array (KoreanChip). 2,729 immune-related genes were selected from Ensembl, Gene Ontology (GO), and KEGG database and 37,398 mapped SNPs were extracted. SNP or PRS-based Cox proportional hazard models were fit for events of overall survival (OS) and progression-free survival (PFS) estimating effect sizes with hazard ratios (HRs). PRS was calculated as effect size weighted sum of risk alleles of individual patients and categorized into tertiles. To investigate enriched pathways, protein-protein interaction networks analysis was conducted. Bonferroni-corrected p-value (1.3 × 10−6) was used as statistically significance threshold. Results: Among 960 CRC patients, 154 (16.0%) occurred events of death and 245 (25.5%) of progression during the follow-up (median=1,698 days, range=7-2,563 days). For OS, a statistically significant associations were mapped to ACTR3B, ST6GAL1, COTL1, PRKCZ, and CAMK1D genes with the strongest SNP rs14808985 (HR=3.07, P=1.87 × 10−7). For PFS, marginal association was mapped to MECOM gene with the strongest SNP rs16854234 (HR=1.48, P=6.13 × 10−6). In PRS analysis, the highest tertile group showed the prominently increased risk for OS (HR=25.0, P<2.0 × 10−16 ) and PFS (HR=5.88, P<2.0 × 10−16 ) compared with the lowest group for a reference. In protein-protein interaction networks analysis, the strongest enrichments were shown in Th17 cell differentiation pathway for OS and in adherences junction for PFS. Conclusions: We identified novel predictive biomarker genetic variants in ACTR3B and MECOM genes associated with OS and PFS, respectively, among CRC patients. Additionally, we presented PRS as a useful biomarker for survival outcomes and suggested enriched biological pathways involved in CRC progression. These knowledges can promote the understanding of CRC survival and the development of immune-related therapeutic interventions for CRC patients in the future. Citation Format: Dabin Yun, Nan Song, Jin-Ah Sim, Min Jung Kim, Ji Won Park, Seung Yong Jeong, Aesun Shin. Novel predictive biomarker SNPs and polygenic risk scores of immune-related genes for colorectal cancer survival in Korea. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5234.
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Hoang, Tung, Min Jung Kim, Ji Won Park, Seung-Yong Jeong, and Aesun Shin. "Abstract 2364: Gut microbiome interacts with clinical characteristics on all-cause mortality of colorectal cancer patients." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2364. http://dx.doi.org/10.1158/1538-7445.am2023-2364.
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Abstract Background: Gut microbiota has been introduced to involve in the migration and invasion stage of metastasis of colorectal cancer (CRC) cells and interact with both the pharmacokinetics and pharmacodynamics of chemotherapeutic agents and immune checkpoint inhibitors. In this study, we examined microbiome features in association with all-cause mortality of CRC patients and examined their interactions with clinical factors. Methods: We performed 16S rRNA sequencing for 331 preoperative fecal samples of CRC patients at Seoul National University Hospital, Korea. Multiple Cox proportional hazard model was applied to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of all-cause mortality due to microbiome features (within-sample diversity indices, species patterns, genus abundance, and taxonomic co-occurrence networks) and clinical factors (tumor grade and stage, surgical methods, neoadjuvant and adjuvant therapies, and invasion). We added the multiplicative term into the model to test the interaction between gut microbiota and clinical characteristics. Results: During a median follow-up of 3.7 years, deaths from any causes were reported in 46 patients. From 172 species, the principal component analysis identified 4 patterns, which explained a total 66.1% variation in species abundance. Of 77 genera, 9 co-occurrence networks were identified by the SParse InversE Covariance Estimation for Ecological Association Inference. For genus level, the risk of death was positively associated with Butyricicoccus (HR=1.54, 95% CI=1.17-2.04), but inversely associated with Lactococcus (HR=0.60, 95% CI=0.37-0.95), Acidaminococcus (HR=0.57, 95% CI=0.34-0.96), Megasphaera (HR=0.79, 95% CI=0.64-0.99), Mitsuokella (HR=0.75, 95% CI=0.57-0.99). All-cause mortality was associated with well or moderately differentiated adenocarcinoma (HR=3.84, 95% CI=1.83-8.07), neoadjuvant therapy (HR=4.10, 95% CI=1.40-12.0), tumor stage IV (HR=8.64, 95% CI=3.42-21.8), and presence of venous invasion (HR=2.32, 95% CI=1.08-4.97). Among clinical pathological factors associated with all-cause mortality, Bacteroides abundance significantly interacted with both tumor stage (pinteraction=0.013) and venous invasion (pinteraction=0.001). Conclusion: Our study identified several microbiome features in links with either increasing or decreasing mortality from any causes. Interactions between the gut microbiome and clinical factors might inform insights on how the gut microbiota modulates the effect of clinical factors on CRC prognosis after the curative operation. Further research using postoperative information is needed to confirm our findings. Citation Format: Tung Hoang, Min Jung Kim, Ji Won Park, Seung-Yong Jeong, Aesun Shin. Gut microbiome interacts with clinical characteristics on all-cause mortality of colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2364.
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Kim, Jwa Hoon, Soohyeon Lee, Min Hee Hong, Jee Hyun Kim, Eun Joo Kang, Tae-Yong Kim, Yeon Hee Park, et al. "Abstract 5209: Hyperprogression in various solid cancers treated with immune checkpoint inhibitors in the real world." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5209. http://dx.doi.org/10.1158/1538-7445.am2022-5209.
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Abstract Purpose: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer prognosis in various cancer types. However, ICIs may trigger accelerated tumor progression, regarded as hyperprogressive disease (HPD), in certain patients, and it is still challenging to define HPD. We aimed to investigate the landscape of HPD and the prognostic value of its different definitions in advanced solid cancer patients treated with ICIs. Methods: We conducted a multicenter, prospective cohort study for solid cancer patients receiving ICIs. Among them, only unresectable or metastatic cancer patients were included in this analysis. Tumor response was evaluated according to RECIST 1.1. In patients who showed progressive disease (PD) by RECIST 1.1 at the first tumor evaluation, HPD was defined according to the following three criteria: A) tumor growth kinetics (TGK) ratio (TGKpost-ICI/TGKpre-ICI >=2, B) >=10mm increase in sum of target lesion (SUMtarget)and at least one of the following two criteria - 1) >=40% increase in SUMtarget or 2) >=20% increase in SUMtarget and the appearance of new lesions in at least two different organs, C) TGK ratio >=2 and >50% increase in SUMtarget. The discriminatory ability of three definitions in terms of overall survival (OS) were evaluated by the chi-square, C-statistics, and prediction error with integrated Brier score. Results: A total of 427 patients were included; head and neck (n=22, 5.2%), lung (n=173, 40.5%), breast (n=8, 1.9%), gastrointestinal tract (n=99, 23.2%), hepatobiliary pancreas (n=57, 13.3%), genitourinary (n=56, 13.1%), melanoma (n=5, 1.2%), and others (n=7, 1.6%). Incidences of HPD were 4.9%, 14.8%, and 11.5% in definition A, B, C, respectively. The incidence of HPD was relatively low (2.7%-9.5%) in non-small cell lung cancer compared to other cancer types (10.1%-21.5% in esophagogastric cancer, 3.9%-21.6% in hepatobiliary pancreas cancer, and 5.5%-22.5% in genitourinary cancer). Median OS was the worst for patients with HPD, which ranged from 4.8 months to 4.9 months according to definition A-C. After multivariate analysis adjusting for cancer types, ICIs types, and the number of prior anti-cancer therapy, each definition remained a significant factor for OS (P<0.001, respectively). Both chi-square and C-statistics of definition B were higher than those of definition A and C, although prediction error with integrated brier scores was similar between three definitions. Conclusions: Incidences of HPD appear to be various according to its definitions and cancer types. Given that the RECIST-based definition B not requiring pre-ICI imaging, showed similar discriminatory ability to predict dismal OS compared to TGK-based ones, it may be the most feasible and convenient measure to capture HPD in daily clinical practice. Citation Format: Jwa Hoon Kim, Soohyeon Lee, Min Hee Hong, Jee Hyun Kim, Eun Joo Kang, Tae-Yong Kim, Yeon Hee Park, Ji-Youn Han, Il-Hwan Kim, Sang-We Kim, Dae Ho Lee, Jae Lyun Lee, Jae Cheol Lee, Chang-Min Choi, Changhoon Yoo, Shinkyo Yoon, Jae Ho Jeong, Seyoung Seo, Sun Young Kim, Jin-Hee Ahn, Sook Ryun Park. Hyperprogression in various solid cancers treated with immune checkpoint inhibitors in the real world [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5209.
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Park, Minsu, Soeun Park, Juyeon Seo, Dongmi Ko, Seongjae Kim, Yong Koo Kang, Kee Dal Nam, et al. "Abstract 6121: UCP2 inhibitor eradicates cancer stem-like population in trastuzumab-resistant HER2-positive breast cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6121. http://dx.doi.org/10.1158/1538-7445.am2023-6121.
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Abstract Purpose: Uncoupling protein 2 (UCP2) is a member of the mitochondrial anion carrier protein family that plays an important role in stabilizing the inner mitochondrial membrane potential (MMP, ΔΨm) and controlling reactive oxygen species (ROS) production. A selective UCP2 inhibitor, genipin is known to elicit cytotoxicity in several cancers, however, its effects on cancer stem cells (CSCs)-like properties and trastuzumab resistance in HER2-positive breast cancer cells have not been fully elucidated. In the present study, we sought to investigate the mechanism of action of genipin responsible for the induction of apoptosis and its effects on CSC-like features, expression of HER family member and trastuzumab resistance in HER2-positive breast cancer cells in vitro and in vivo. Experimental Designs: The effects of genipin on trastuzuamb-sensitive [BT474 and SKBR3] and trastuzumab-resistant [JIMT-1 and MDA-MB-453] HER2-positive breast cancer cell lines in vitro were evaluated for cell viability, Sub-G1, ROS, MMP, ALDH1 activity, CD44+/CD24- subpopulation and mammosphere formation. To confirm the physiological relevance of our in vitro observations, we explored the impact of genipin on tumor growth and angiogenesis and expression of p95HER2 and ALDH1A1 in trastuzumab-resistant xenograft model in vivo. Results: HER2-positive breast cancer cells harbored a higher level of UCP2, when compared to their counterparts. Genipin significantly downregulated UCP2 and mitochondrial dysfunction coinciding with increased ROS generation and disruption of MMP. These phenomena were accompanied with upregulation of the Bax/Bcl-2 ratio and activation of caspase-3 and caspase-7. Genipin treatment led to significant reduction in levels of truncated p95HER2, p-HER2, p-HER3 and p-Akt levels in both trastuzumab-sensitive and -resistant lines. Marked decline of CD44 and ALDH1A1 expression by genipin treatment was associated with attenuation of mammosphere-forming ability. UCP2 level is predominantly upregulated in CSC-enriched populations, while its knockdown significantly suppressed CSC-like characteristics concomitant with decreased ALDH1A1 and CD44 expression as well as impairment of ALDH1 activity. Genipin administration significantly retarded tumor growth and angiogenesis in trastuzumab-resistant JIMT-1 xenograft tumors. The antitumor effect occurred concomitantly with a decrease in Ki-67 proliferating index and enhancement of apoptosis. Furthermore, individuals receiving genipin exhibited markedly lower levels of p95HER2, full-length p185HER2, CD44 and ALDH1A1 expression compared to their control counterparts. Conclusion: To our knowledge, our findings are the first reported instance of genipin-induced suppression of CSC-like properties and HER2/HER3/Akt axis, implying that genipin treatment may have application in addressing trastuzumab resistance. Citation Format: Minsu Park, Soeun Park, Juyeon Seo, Dongmi Ko, Seongjae Kim, Yong Koo Kang, Kee Dal Nam, So Ra Seuk, Tae-Min Cho, Eunsun Jung, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo. UCP2 inhibitor eradicates cancer stem-like population in trastuzumab-resistant HER2-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6121.
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Park, Hyeree, Tung Hoang, Min Jung Kim, Ji Won Park, Seung-Yong Jeong, and Aesun Shin. "Abstract 5892: Microbial diversity and composition according to short-term postoperative complication status in colorectal cancer patients." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5892. http://dx.doi.org/10.1158/1538-7445.am2023-5892.
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Abstract Background: Previous studies have suggested the disturbance in the microbial composition followed by dysbiosis contribute to the onset of gastrointestinal malignancies, including colorectal cancer (CRC). However, the impact of microbiome on short-term postoperative complications after CRC surgery is not well investigated. This study aimed to investigate whether the gut microbial diversity and composition in CRC patients were associated with the occurrence of short-term postoperative complications. Methods: We linked the clinical data and preoperative sequencing data of fecal samples of 331 patients who underwent CRC surgery from 2017 to 2019 in Seoul National University Hospital. Short-term postoperative complications were defined as first complications that developed within 30 days of surgery. We used linear discriminant analysis (LDA) of effect size (LEfSe) in the Galaxy webserver to identify enriched bacteria in patients with and without complications. Then, we calculated microbial dysbiosis index (MDI) by each patient and compared them according to the complication status. Wilcoxon rank sum test was conducted to compare the alpha diversity indices according to the complication event. Subgroup analyses according to types of complications were also performed: surgical procedure-related (SP) group and nonsurgical procedure-related (NSP) group. Results: Overall, 84 patients (25%) developed short-term postoperative complications: SP group (n=39) and NSP group (n=45). From the LEfSe analysis, Bacteroides uniformis (LDA score: 3.64, p-value 0.04) and Clostridium colicanis (LDA score: 3.39, p-value 0.01) were enriched in patients who developed short-term complications, whereas Roseburia faecis (LDA score: 3.26, p-value 0.05), Bifidobacterium bifidum (LDA score: 2.98, p-value 0.03), Faecalibacterium sp. (LDA score: 3.12, p-value 0.02) and Prevotella nigrescens (LDA score: 2.87, p-value 0.05) were enriched in patients without complications. When compared with patients without complications, taxa related to class Gammaproteobacteria, genus Clostridium, species Roseburia faecis, and Desulfovibrio D168 were abundant in the SP group. Alpha diversity indices were not significantly different according to the complication status or the type of complication. MDI from the enriched bacteria were significantly higher in patients with complications compared to those without complications (p-value<0.001), and MDI of the SP group were also significantly higher than that of patients free of complications (p-value 0.001). Conclusion: Our study suggests a potential relationship between microbial composition and surgical outcome in CRC patients. No significant difference in alpha diversity was observed according to the occurrence or the type of complication. Further studies are needed to investigate the postoperative changes of microbial features. Citation Format: Hyeree Park, Tung Hoang, Min Jung Kim, Ji Won Park, Seung-Yong Jeong, Aesun Shin. Microbial diversity and composition according to short-term postoperative complication status in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5892.
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Park, Hyeree, Min Jung Kim, Ji Won Park, Seung-Yong Jeong, Aesun Shin, Sung-Yup Cho, Eun Sung Jung, Dong Ho Suh, Sunyoung Lee, and Yu Jin Park. "Abstract 2804: Comparative analysis of microbial diversity and abundance in colorectal cancer patients before and after surgery." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2804. http://dx.doi.org/10.1158/1538-7445.am2024-2804.
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Abstract Background: Previous studies have indicated differing patterns of the microbiome in colorectal cancer (CRC) patients compared to healthy individuals. Yet, the changes in microbial features of CRC patients before and after surgery remain underexplored. This study aims to investigate the impact of surgical intervention on the gut microbial diversity and abundance at the patient level. Methods: This hospital-based study analyzed data from 36 CRC patients who underwent CRC surgery at the Department of Surgery, Seoul National University Hospital between January 2020 and May 2022. Fecal samples from these patients were collected twice, both before surgery and during the post-surgery follow-up period. DNA extraction from stool specimens was performed using the MAG-Bind Universal Pathogen kit. This was followed by amplification and sequencing of the 16S rRNA gene V3-V4 region, with subsequent bioinformatics analyses conducted using QIIME 2. To compare the alpha diversity indices of patients before and after surgery, we employed both the paired t-test and the Wilcoxon signed-rank test. Results: Out of the 36 patients, 21 were male and 15 were female, with a mean age of 63.8 years. The average duration between surgery and post-surgery fecal sample collection was 2.3 years. Post-surgery, the alpha diversity indices decreased compared to pre-surgery, but the differences were not significant, except for Faith's PD. At the phylum level, Firmicutes and Actinobacteriota, both recognized as beneficial bacteria, increased in abundance after surgery, while Bacteriodota, typically considered harmful, significantly decreased. At the genus level, variations in microbial abundance also showed an increase in Blautia, Bifidobacterium, and Collinsella, and a decrease in Enterococcus, Romboutsia, and Faecalibacterium. The rise in Bifidobacterium abundance following surgery suggests a gut environment altered by the surgery to favor beneficial bacteria. However, a specific species decline in Bifidobacterium adolescentis was observed, highlighting that CRC surgery may have distinct impacts on different bacterial species. Conclusions: Our study indicates a slight decline in gut microbiome diversity following surgery. At the phylum level, there was an observed increase in beneficial bacteria and a decrease in harmful bacteria post-surgery, suggesting potential health improvements in CRC patients. Further research, particularly with a larger sample size and encompassing a broader range of bacteria, is needed to better understand the patterns and implications of microbiome variation in relation to surgical outcomes. Such insights could be pivotal in optimizing patient care and recovery strategies post-surgery. Citation Format: Hyeree Park, Min Jung Kim, Ji Won Park, Seung-Yong Jeong, Aesun Shin, Sung-Yup Cho, Eun Sung Jung, Dong Ho Suh, Sunyoung Lee, Yu Jin Park. Comparative analysis of microbial diversity and abundance in colorectal cancer patients before and after surgery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2804.
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Cheng, Ying, Jie Wang, Caicun Zhou, Wenxiu Yao, Qiming Wang, Xuhong Min, Gongyan Chen, et al. "Abstract CT038: Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage SCLC: A phase 3 trial." Cancer Research 82, no. 12_Supplement (June 15, 2022): CT038. http://dx.doi.org/10.1158/1538-7445.am2022-ct038.
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Abstract Introduction: Extensive-stage small cell lung cancer (ES-SCLC) is associated with limited treatment options and poor prognosis. Immunotherapy has recently showed robust clinical activity in ES-SCLC. In this double-blind, phase 3 trial, we evaluated adebrelimab (SHR-1316), a novel anti-PD-L1 antibody, in combination with standard chemotherapy (chemo) as first-line treatment for ES-SCLC. Methods: Patients naïve to systemic treatment for ES-SCLC were randomized 1:1 to receive 4-6 cycles of adebrelimab (20 mg/kg, iv, d1, q3w) or placebo with carboplatin (AUC 5, d1, q3w) plus etoposide (100 mg/m2, d1, d2, d3, q3w), followed by maintenance therapy with adebrelimab or placebo. The primary endpoint was overall survival (OS). Results: 462 patients were randomized and treated (adebrelimab+chemo, n=230; placebo+chemo, n=232). As of Oct 08, 2021, with an median follow-up of 13.5 mo (all patients; 22.5 mo for patients alive), OS was significantly prolonged with adebrelimab+chemo vs placebo+chemo (median, 15.3 mo [95% CI 13.2-17.5] vs 12.8 mo [95% CI 11.3-13.7]; hazard ratio [HR], 0.72 [95% CI 0.58-0.90], 1-sided p=0.0017); OS rate was 62.9% vs 52.0% at 12 mo and 31.3% vs 17.2% at 24 mo. Progression-free survival (PFS) per independent review committee (IRC) was 5.8 mo (95% CI 5.6-6.9) with adebrelimab+chemo vs 5.6 mo (95% CI 5.5-5.7) with placebo+chemo (HR 0.67, 95% CI 0.54-0.83); PFS rate was 49.4% vs 37.3% at 6 mo and 19.7% vs 5.9% at 12 mo. Objective response rate (ORR) and duration of response (DoR) also favored the adebrelimab+chemo group (Table 1). Grade ≥3 treatment-related adverse events occurred in 85.7% vs 84.9% of patients with adebrelimab+chemo vs placebo+chemo, with the most common (frequency ≥5%) being hematological toxicities in both groups. Conclusions: The addition of adebrelimab to chemotherapy significantly improved OS with an acceptable safety profile, supporting this combination as a new first-line treatment option for ES-SCLC. Efficacy outcomes Adebrelimab+Chemo (n=230) Placebo+Chemo (n=232) Median OS (95% CI), mo 15.3 (13.2-17.5) 12.8 (11.3-13.7) HR (95% CI)*, 1-sided log-rank p 0.72 (0.58-0.90); p=0.0017 12-mo OS rate (95% CI), % 62.9 (56.3-68.8) 52.0 (45.4-58.2) 24-mo OS rate (95% CI), % 31.3 (24.9-37.9) 17.2 (12.1-23.0) Median PFS (95% CI), mo 5.8 (5.6-6.9) 5.6 (5.5-5.7) HR (95% CI)*, 1-sided log-rank p 0.67 (0.54-0.83); p <0.0001 6-mo PFS rate (95% CI), % 49.4 (42.4-56.0) 37.3 (30.7-43.9) 12-mo PFS rate (95% CI), % 19.7 (14.5-25.5) 5.9 (3.1-10.1) IRC-assessed ORR (95% CI), % 70.4 (64.1-76.3) 65.9 (59.5-72.0) Median DoR (95% CI), mo 5.6 (4.6-6.7) 4.6 (4.3-5.5) *Stratified Cox proportional-hazards model Citation Format: Ying Cheng, Jie Wang, Caicun Zhou, Wenxiu Yao, Qiming Wang, Xuhong Min, Gongyan Chen, Xingxiang Xu, Xingya Li, Fei Xu, Yong Fang, Runxiang Yang, Guohua Yu, Youling Gong, Jun Zhao, Yun Fan, Quan Liu, Lejie Cao, Yu Yao, Yunpeng Liu, Xiaoling Li, Jingxun Wu, Zhiyong He, Kaihua Lu, Liyan Jiang, Huiqing Yu, Chengping Hu, Wenhua Zhao, Jian Zhao, Gang Wu, Dingzhi Huang, Chengshui Chen, Cuimin Ding, Baihong Zhang, Xiuwen Wang, Hui Luo, Baolan Li, Ben Zhang, Haowen Li, Ke Ma. Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage SCLC: A phase 3 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT038.
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Park, Su-Bin, Ji-Sik Kang, Min-Je Kim, Shin-Wha Lee, Dong-Woo Kang, and Yong-Man Kim. "Abstract 6190: Anti-tumor effects of lenvatinib plus anti-PD-1 in syngeneic murine cervical cancer models." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6190. http://dx.doi.org/10.1158/1538-7445.am2022-6190.
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Abstract Immune checkpoint inhibitors (ICIs) have been applied in patients with various solid tumors since they were approved by U.S. FDA in 2011. However, only less than 20% of patients benefit from ICIs including anti-programmed cell death protein 1 (aPD-1). Recently, many studies to improve the response of ICIs are in progress, and especially, vascular endothelial growth factor receptors (VEGFR) pathway was emerged as major target. VEGFR inhibitors regulate the differentiation of tumor-associated macrophage, antigen presenting dendritic cell, and T cell infiltration, so they make a synergic antitumor effect with ICIs. In this study, we investigated the effect of lenvatinib combined with anti-mouse PD-1 in syngeneic murine cervical cancer models to show whether VEGFRi enhance the antitumor effect of ICIs. We established syngeneic mouse models of cervical cancer to confirm synergic effect by lenvatinib combined with aPD-1. 1x107 cells of U14 cells were injected subcutaneously into the flanks of BALB/c wild- type (immunocompetent) mice and BALB/c nude (immunocompromised) mice. They were treated with lenvatinib when the tumor volume reached at 200 mm3, subsequently, aPD-1 was administered in immunocompetent mice. We administrated lenvatinib (10 mg/kg, orally, daily) and aPD-1(200 µg per mouse, intraperitoneally (I.P), twice a week) for 3 weeks. Tumor volume was measured twice a week. After the end of the experiment, we harvested tumors and spleens, and performed histological analysis. All experiments were approved by the Institutional Animal Use and Care Committee (IACUC) in Asan Institute for Life Science.Although the tumor was increased despite lenvatinib treatment in immunocompromised model with BALB/c nude mice, on the 17th day after injection, the tumor growth was inhibited in lenvatinib group compared with vehicle group (2914 mm3 vs. 3663 mm3, respectively) (P=0.0014). On the other hand, the tumor volume was significantly reduced by lenvatinib in the immunocompetent model (278 mm3 in Len vs. 490 mm3 in Veh) (P=0.0347), particularly the tumor size was decreased since 2 weeks of injection. Subsequently, we investigated the synergistic effects of combination with lenvatinib and aPD-1 in immunocompetent model. Each single treatment group showed the reduction of tumor volume compared to vehicle group (278 mm3 in Len and 258 mm3 in aPD-1 vs. 490 mm3 in Veh). Furthermore, the lenvatinib plus aPD-1 combination group reduced tumor volume to 110mm3 on the 24th day after injection and it was significantly different compared to each single treatment group (P=0.13868 and P=0.27385, respectively).In this study, anti-tumor effect of aPD-1 was enhanced by the regulation of tumor microenvironment with lenvatinib in immunocompetent murine cervical cancer models. In conclusion, addition of lenvatinib is expected to increase the efficacy of ICIs in patients with cervical cancer who have the resistance or insensitivity to ICIs. Citation Format: Su-Bin Park, Ji-Sik Kang, Min-Je Kim, Shin-Wha Lee, Dong-Woo Kang, Yong-Man Kim. Anti-tumor effects of lenvatinib plus anti-PD-1 in syngeneic murine cervical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6190.
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Lee, Dae-Won, Sae-Won Han, Yoojoo Lim, Hwang-Phill Kim, Hanseong Roh, Min Jung Kim, Seung-Bum Ryoo, et al. "Abstract 5157: ctDNA change predicts treatment outcome of regorafenib in metastatic colorectal cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5157. http://dx.doi.org/10.1158/1538-7445.am2022-5157.
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Abstract Introduction: Regorafenib is a multikinase inhibitor which showed clinical benefit in patients with treatment refractory metastatic colorectal cancer. However, as only a subset of patients derives clinical benefit from regorafenib, it is essential to identify biomarker to predict therapeutic response. Circulating tumor DNA (ctDNA) is emerging as a valuable non-invasive tool to identify tumor heterogeneity and tumor burden. This study investigated ctDNA dynamics in patients with metastatic colorectal cancer treated with regorafenib. Methods: This is a prospective biomarker study including patients with refractory metastatic colorectal cancer treated with regorafenib (ClinicalTrial.gov Identifier: NCT01996969). Patients with metastatic colorectal cancer who were refractory to standard therapies (fluoropyrimidine, oxaliplatin, and irinotecan) were eligible for the current study. Patients received oral regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle and were treated until disease progression, death, unacceptable toxicity, or decision by the treating physicians. Blood samples were obtained prior to regorafenib treatment and after every two cycles of regorafenib treatment until disease progression. ctDNA was detected by AlphaLiquid® 100 target capture panel (IMBdx, Inc., Seoul, South Korea). Alphaliquid® 100 is a tumor agnostic panel consist of 106 genes, including 10 gene fusion and MSI. Variant allele frequency (VAF) amount was calculated by adding the VAF value of all altered genes. Results: A total of 110 patients were included in the present study. Baseline blood samples were successfully acquired in 107 patients (97.3%) with a total of 713 genetic alteration. Mutation was most frequently found in TP53 (76.6%) followed by APC (75.7%), KRAS (43.0%), PIK3CA (17.8%), and SMAD4 (17.8%). BRAF mutation was found in 8.4% of patients and NRAS was detected in 3.7% of patients. Blood samples after two cycle of regorafenib was acquired in 106 patients, and was acquired in 95 patients after disease progression. Among 104 patients with baseline and follow-up cfDNA, the mean VAF at baseline was 12.8% and 7.2% in follow-up. This resulted in a mean VAF change of -5.61% (absolute value) and -43.7% (relative change). VAF decreased markedly after 2 cycles of regorafenib in several genes, including CSF1R, JAK3, KIT, ROS1, and TERT. Although, VAF change of specific gene was not associated with regorafenib outcome, VAF change of whole gene was an early predictive marker for regorafenib. Reduction in VAF amount of ≥ 50% after two cycles of regorafenib were associated with a significantly improved PFS (6.1 vs. 2.7 months, p = 0.002), OS (11.3 vs. 5.9 months, p = 0.001), and higher disease control rate (86.3% vs. 51.1%, p < 0.001). Conclusions: Serial ctDNA could be used as an early predictive biomarker in metastatic colorectal cancer treated with regorafenib. Citation Format: Dae-Won Lee, Sae-Won Han, Yoojoo Lim, Hwang-Phill Kim, Hanseong Roh, Min Jung Kim, Seung-Bum Ryoo, Ji Won Park, Seung-Yong Jeong, Kyu Joo Park, Gyeong Hoon Kang, Tae-You Kim. ctDNA change predicts treatment outcome of regorafenib in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5157.
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Ryu, Jai Min, Han-Byoel Lee, Sei Hyun Ahn, Il-Yong Chung, Seeyoun Lee, Seho Park, Woosung Lim, et al. "Abstract PS01-03: What to expect from the No axillary surgical treatment for lymph node-negative patients after ultra-sonography [NAUTILUS] trial (KBCSG-21): Clinicopathologic characteristics and axillary lymph node status of enrolled patients." Cancer Research 84, no. 9_Supplement (May 2, 2024): PS01–03—PS01–03. http://dx.doi.org/10.1158/1538-7445.sabcs23-ps01-03.
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Abstract Purpose: The primary role of sentinel lymph node biopsy (SLNB) for early breast cancer (BC) is axillary staging. In terms of clearance of axillary disease or prevention of recurrence, its role may be limited considering the low axillary recurrence rate of less than 2% even though false-negative rates are 5-10% and the 25% additional axillary lymph node (ALN) detection in the ALND arms of the ACOSOG Z0011 and AMAROS trials. The NAUTILUS trial (NCT04303715) randomized cT1-2/N0 BC patients planned for breast-conserving surgery to evaluate the non-inferiority of omitting SLNB regarding 5-year invasive disease-free survival. The secondary endpoints are overall survival, distant metastasis-free survival, axillary recurrence rate, and quality of life of the patients. We aimed to investigate the clinicopathologic characteristics and ALN status of the subjects enrolled in the NAUTILUS trial. Methods: NAUTILUS trial randomized 1,734 subjects into SLNB or no-SLNB arms from September 2020 to October 2022. Axillary ultrasonography was mandatory to determine clinical N0, defined as no suspicious ALN or no tumor on ultrasound-guided biopsy of suspicious ALN. Clinicopathologic variables and the ALN status of the SLNB arm were analyzed. Results: Among 1,734 enrolled subjects, 828 (50.3%) and 818 (49.7%) subjects in the SLNB and no-SLNB arms, respectively, were included for analysis. Clinical and pathologic T stage, hormonal receptor/HER2 status, histologic grade, age, menopausal status, and Ki-67 were evenly distributed between the two groups (p = 0.554, 0.350, 0.056, 0.369, 0.623, 0.725 and 0.214, respectively). Median age was 55.3 (range, 48.0-62.0) years, and 661 (40.2%) were premenopausal. Overall, 30 (1.8%), 1,382 (84.0%), and 229 (13.9%) subjects were pTmic, pT1, and pT2, respectively, and median tumor size was 1.3 cm (range, 0.1-5.0). In the SLNB group, 94 (11.4%) had ALN metastasis, of which 9 (1.1%), 78 (9.4%), and 5 (0.6%) were pN1mic, pN1, and pN2-3, respectively (Table 1). According to pathologic tumor size, 5.8% (16/279), 11.4% (48/421), and 23.8% (30/126) were ALN positive for ≤ 1.0 cm, >1.0cm & ≤ 2.0 cm, and > 2.0 & ≤ 5.0 cm, respectively. The clinical and pathologic tumor size distribution among subjects with ALN metastasis were 23 (24.5%), 43 (45.7%), 9 (9.6%) and 16 (17.0%), 48 (51.1%), 30 (31.9%), respectively, for ≤ 1.0 cm, >1.0cm & ≤ 2.0 cm, and > 2.0 & ≤ 5.0 cm (Table 2). Among them, 12 (12.8%) received subsequent ALND. There was no difference in ALN metastasis rate according to molecular subtype, histologic grade, age, menopausal status, and Ki-67 (p= 0.812, 0.204, 0.671, and 0.101, respectively). Conclusions: The NAUTILUS trial completed enrollment of 1,734 subjects, among which 1,646 are available to analyze basic clinicopathologic characteristics. The trial included 229 (13.9%) pT2 and 661 (40.2%) premenopausal subjects and is expected to show the impact of SLNB omission in these subgroups. Data lock is expected in October 2027. Patients characteristics SLNB, sentinel lymph node biopsy; LVI, lymphovascular invasion; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; HER2, anti-human epidermal growth factor-2; BCS, breast conserving surgery; TM, total mastectomy; ALND, axillary lymph node dissection Basic characteristics for sentinel lymph node biopsy group a revealed no lymph node metastasis by fine needle aspiration or gun biopsy ALN, axillary lymph node; LN, lymph node Citation Format: Jai Min Ryu, Han-Byoel Lee, Sei Hyun Ahn, Il-Yong Chung, Seeyoun Lee, Seho Park, Woosung Lim, Joon Jeong, Jeong Eon Lee, Eunhye Kang, Ji Hyun Chang, Jung Min Chang, Woo Kyung Moon, Wonshik Han, Eun-Kyu Kim. What to expect from the No axillary surgical treatment for lymph node-negative patients after ultra-sonography [NAUTILUS] trial (KBCSG-21): Clinicopathologic characteristics and axillary lymph node status of enrolled patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS01-03.