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  • American Association for Cancer Research (AACR)  (10)
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  • 1
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    Online Resource
    Abstract CT038: Comprehensive molecular characterization of clinical response to durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: A phase 2 clinical trial
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT038-CT038
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT038-CT038
    Abstract: We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in soft tissue sarcoma (STS). Further, we performed molecular characterisation with whole exome and transcriptomic sequencing to identify the determinants of response. In this single-arm, phase 2 trial (NCT#03798106), we enrolled patients with metastatic and/or recurrent STS who had received up to two previous lines of systemic anticancer therapy and had at least one measurable lesion. Treatment consisted of pazopanib 800 mg orally, administered once a day, continuously, and durvalumab 1500 mg administered via intravenous infusion once every 3 weeks. The primary endpoint was the overall response rate. Between September 2019 and October 2020, fourteen (30.5%) of the 46 evaluable patients showed an objective response, including in alveolar soft-part sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, and desmoplastic small round cell tumour. During a median follow-up period of 18.4 months, the median progression-free survival (PFS) was 7.7 months (95% confidence interval: 5.7-10.4). The common treatment-related adverse events of grades 3-4 included neutropenia (n = 9), elevated aspartate aminotransferase (n = 7) and alanine aminotransferase (n = 5) levels, and thrombocytopenia (n = 4). In the exploratory analysis, the B lineage signature was a significant key determinant of overall response (P=0.014). In situ analysis also showed that tumours with high CD20+ B cell infiltration and vessel density had a longer PFS than those with low B cell infiltration and vessel density (P=6.5 × 10−4) as well as better response (50% vs 12%, P=0.019). In conclusion, durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile. Our findings provide insights into combined high B cell infiltration and vessel density as potentially relevant biomarkers for the selection of patients who may benefit to a greater extent from PD-L1 blockade and VEGF inhibitor combination. Citation Format: Hee Jin Cho, Kum-Hee Yun, Su-Jin Shin, Young Han Lee, Seung Hyun Kim, Wooyeol Baek, Yoon Dae Han, Sang Kyum Kim, JooHee Lee, Iksung Cho, Heounjeong Go, Jiwon Ko, Inkyung Jung, Min Kyung Jeon, Hyang Joo Ryu, Sun Young Rha, Hyo Song Kim, Hyun Jung Jun. Comprehensive molecular characterization of clinical response to durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: A phase 2 clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT038.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-CT038
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
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    Abstract 3040: A modified microbiota-accessible carbohydrates diet could change gut microbiota in patients with colorectal cancer after surgery
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3040-3040
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3040-3040
    Abstract: Dietary factors have important role in modulating the gut microbiome, which in-turn regulates the molecular events in colonic mucosa. The composition and resulting metabolism of the gut microbiome are decisive factors in colorectal cancer (CRC) tumorigenesis. Microbiota-Accessible Carbohydrates (MAC) refer to carbohydrates that the human intestine cannot digest, but that can be digested by intestinal microbes. During that process, short chain fatty acid (SCFA) is produced, which is known to increase beneficial intestinal bacteria and decrease inflammation around intestinal cells. This prospective, longitudinal study aims to explore the changes in the composition and diversity of intestinal microbiota according to the diet pattern in patients with stage I to lll CRC. Participants were assigned to 3-week modified MAC diet group or free diet group followed by diet switching for 3 weeks. Modified MAC diet was designed to adapt to a high fiber diet including 30g of dietary fiber daily and delivered to the patient’s home for 3 weeks as a meal kit supported by Dr. Kitchen Corp. We collected 113 fecal samples from 40 CRC patients before and after diet switching. To explore the effect of diet on the composition of the microbiota and pattern of defecation, 16S rRNA sequencing were performed using fecal samples. Biological information was processed by Qiime2 plugins, DESeq2 and Lefse. Among total 40 participants, 26 (65%) were male. There were 11 (27.5%) with right colon cancer and 29 patients with left colon and rectal cancer. 18 patients without adjuvant chemotherapy were lower stage and higher compliance to modified MAC diet (median 89%) than 22 patients with adjuvant chemotherapy (median 60%). In all participants, protein and dietary fiber intake increased by more than 90% and sodium intake decreased by more than half during modified MAC diet compared to the free diet. There was no difference in alpha diversity change between chemotherapy group and non-chemotherapy group but a significant difference was observed in beta diversity change. Especially, Lachnospiraceae Eubacterium hallii were enriched in non-chemotherapy group. During the modified MAC diet in the group not receiving chemotherapy, Lactobacillaceae Pediococcus, Prevotellaceae Prevotella, Streptococcaceae Lactococcus were increased and Ruminococcaceae Eubacterium siraeum group, Ruminococcaceae UBA1819 were decreased. This study results showed that 3 weeks dietary intake influences the structure and activity of gut microbiome even though the dietary responsiveness of the individual’s microbiota varied substantially. The joint study of microbiome and metabolome has been ongoing now as the most promising approach to evaluate host-microbiome interaction. In order to prove the importance of a balanced diet after colorectal cancer surgery, it will be necessary to analyze the relationship with clinical outcomes. Citation Format: Boyeon Kim, Jiwon Lee, Jin Kim, Jung-Myun Kwak, Hye-Jin Cho, Eun Sung Jung, Sunyoung Lee, Dong Ho Suh, Yu Jin Park, Soohyeon Lee. A modified microbiota-accessible carbohydrates diet could change gut microbiota in patients with colorectal cancer after surgery [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 3040.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-3040
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
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    Tumor Microenvironment Remodeling by Intratumoral Oncolytic Vaccinia Virus Enhances the Efficacy of Immune-Checkpoint Blockade
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 5 ( 2019-03-01), p. 1612-1623
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 5 ( 2019-03-01), p. 1612-1623
    Abstract: Cancer immunotherapy is a potent treatment modality, but its clinical benefit depends on the tumor's immune profile. Here, we used mJX-594 (JX), a targeted and GM-CSF–armed oncolytic vaccinia virus, as a strategy to remodel the tumor microenvironment (TME) and subsequently increase sensitivity to αPD-1 and/or αCTLA-4 immunotherapy. Experimental Design: The remodeling of the TME was determined using histologic, flow-cytometric, and NanoString immune profiling analyses. JX was intratumorally injected into implanted Renca kidney tumors or MMTV-PyMT transgenic mouse breast cancers with or without αPD-1 and/or αCTLA-4. Various combination regimens were used to evaluate immunotherapeutic anticancer responses. Results: Intratumoral injection of JX remodeled the TME through dynamic changes in the immune system, as shown by increased tumor-infiltrating T cells and upregulation of immune-related gene signatures. This remodeling induced conversion of a noninflamed tumor into an inflamed tumor. JX virotherapy led to enhanced abscopal effects in distant tumors, with increased intratumoral infiltration of CD8+ T cells. A depletion study revealed that GM-CSF is an indispensable regulator of anticancer efficacy of JX. Dual-combination therapy with intratumoral JX and systemic αPD-1 or αCTLA-4 further enhanced the anticancer immune response, regardless of various treatment schedules. Of note, triple combination immunotherapy with JX, αPD-1, and αCTLA-4 elicited the most potent anticancer immunity and induced complete tumor regression and long-term overall survival. Conclusions: Our results show that intratumoral JX treatment induces dramatic remodeling of the TME and more potently suppresses cancer progression with immune-checkpoint blockades by overcoming resistance to immunotherapy.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-1932
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 4
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    Abstract 6468: Association of food groups and dietary pattern with breast cancer risk: A systematic review and meta-analysis
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6468-6468
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6468-6468
    Abstract: We conducted a systematic review and meta-analysis of current evidence for the association between food groups, dietary patterns, and breast cancer risk among the Asian population. This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We performed a systematic literature search up to November 2022 in English in the PubMed, Web of Science, Embase, and Cochrane databases. Risk ratios (RRs) with 95% confidence intervals (CIs) were extracted as effect sizes. Publication bias was estimated by the funnel plot method. We collected the data from 15 cohort studies and 30 case-control studies meeting the search criteria. The meta-analysis found that fruit and vegetable consumption was associated with a 27% and 35% lower risk of breast cancer, respectively [RR = 0.73 (0.56, 0.96); RR = 0.65 (0.47, 0.90)]. By contrast, no significance was found between meat, soy food, and green tea consumption and breast cancer risk (P & gt; 0.05). However, soy protein and isoflavone intake could lower breast cancer risk by 35% and 32%, respectively [RR = 0.65 (0.51, 0.83); RR = 0.68 (0.55, 0.82)]. As for dietary pattern, higher adherence to a healthy dietary pattern and healthy eating index was associated with a 38% and 62% reduction in breast cancer risk, respectively [RR = 0.62 (0.44, 0.88; RR = 0.38 (0.22, 0.67)] , while high adherence to an unhealthy dietary pattern was associated with a 44% increased risk [RR = 1.44 (1.06, 1.96)]. Considering alcohol consumption, a 75% increased risk of breast cancer was found [RR= 1.75 (1.33, 2.30)] . The present meta-analysis found that high intakes of fruit, vegetable, soy protein, and soy isoflavone significantly reduced the risk of breast cancer, while high intake of alcohol had a significantly increased risk. Meat, soy food, and green tea consumption were not significantly associated with breast cancer risk. Considering dietary patterns, higher adherence to a healthy eating index and a healthy dietary pattern may reduce breast cancer risk. Conversely, adherence to unhealthy dietary patterns may increase breast cancer risk. However, further studies are needed to confirm the associations between dietary patterns and breast cancer in the Asian population. This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No.2022R1F1A1074279). MSIT: Ministry of Science and ICT. Citation Format: Jialei Fu, Woo-Kyoung Shin, Dan Huang, Sukhong Min, Li-Juan Tan, Hyein Jung, Khongorzul Ganbat, Jiwon Jeong, Seok-Jae Oh, Bayarmaa Nasan Ulzii, Daehee Kang, Sangah Shin. Association of food groups and dietary pattern with breast cancer risk: A systematic review and meta-analysis [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 6468.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-6468
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Abstract PO-079: Fused LASSO application for gastric cancer image segmentation
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 5_Supplement ( 2021-03-01), p. PO-079-PO-079
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 5_Supplement ( 2021-03-01), p. PO-079-PO-079
    Abstract: Despite recent advances in digital pathology, the development of a robust deep learning model for identifying tumor regions on digitalized slide images has been plagued by problems related to the patch-based approach attributable to the narrow and limited field-of-views. In this study, we explored the effect of the fused lasso technique on diagnostic performance using gastric cancer pathology images. Our goal is to develop a speedy tumor segmentation scheme that overcomes performance degradation arising from the limitations of the patch-based approach. We used 27 specimens with partial annotation from tissue-microarrays (TMAs) with gastric cancer from the Asan Medical Center. Our segmentation adjustment method was tested on multiple renowned deep learning model architectures to detect malignancy on tissue slides. In the fused lasso formulation, fusion and lasso penalty were adopted to penalize variables with L1-norms based on both the patchwise predictions and their pairwise differences between adjoining patches. To obtain well-structured boundaries and discard irrelevant observations, the best performing hyperparameters controlling the degree to be penalized were adaptively determined via cross-validation. We demonstrated that adoption of fused lasso penalties can produce segmentation close to that generated by experts without a significant increase in computing time. The average test performance in terms of IOU, dice, accuracy, precision, recall, and AUROC increased by a degree of 3.74%p, 3.27%p, 0.93%p, 5.32%p, 3.20%p, and 1.58%p, respectively. This study provides a use case of the application of fused lasso modeling for precisely identifying tumor area, which can alleviate the bottleneck in gastric cancer research. Citation Format: Jiwon Jung, Jin Roh, Chan-Sik Park. Fused LASSO application for gastric cancer image segmentation [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-079.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.ADI21-PO-079
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 6
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    Abstract 5428: Effect of amentoflavone on Nrf2 signaling in HaCaT cells
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5428-5428
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5428-5428
    Abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key mediator of cell response to oxidative stress and xenobiotics. Multiple lines of evidence suggest that Nrf2 activation protects against many diseases, aging, inflammation, and cancer. To date, Nrf2 activators from natural products have been widely studied. In this study we investigated the potential effect of Amentoflavone (AFN), a biflavonoid in many natural plants, on Nrf2 signaling in human keratinocytes cells (HaCaT). As results, AFN significantly increased ARE-luciferase activity and nuclear accumulation of Nrf2. Furthermore, a Nrf2 target protein, NQO-1, was significantly increased by AFN in dose- and time-dependent manner. To verify the Nrf2 signaling mechanism by AFN, firstly we measured reactive oxygen species (ROS) using DCFDA because mild intracellular ROS could stimulate Nrf2 activation. Surprisingly AFN triggered the production of ROS in 1 h and AFN-induced Nrf2 was inhibited by N-acetyl cysteine (NAC). Thus, we studied the ROS-related signaling on Nrf2 by measuring the activation of Akt and mitogen-activated protein (MAP) kinase family such as extracellular signal-regulated kinase (ERK) and p38. As results, pharmacology inhibitor of PI3K/Akt (LY294002) or p38 (SB 203580), but not ERK (U0126), abrogated AFN-activated Nrf2. Furthermore, silencing p38 using p38siRNA or inhibition using its pharmacology inhibitor decreased phosphorylation of Akt and attenuated Nrf2 activation. We also confirmed that AFN stabilized Nrf2 by inhibiting the ubiquitination. Taken together, AFN activates Nrf2 through ROS-mediated phosphorylation of p38 and followed by phosphorylation of Akt. Citation Format: Lilik Duwi Wahyudi, Jiwon Jeong, Heejung Yang, Jung-Hwan Kim. Effect of amentoflavone on Nrf2 signaling in HaCaT cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018 ;78(13 Suppl):Abstract nr 5428.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-5428
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 7
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    Abstract PO-34: Subcutaneous panniculitis-like T-cell lymphoma with HAVCR2 mutation shows unique clinicopathologic features and gene expression profile
    American Association for Cancer Research (AACR) ; 2020
    In:  Blood Cancer Discovery Vol. 1, No. 3_Supplement ( 2020-11-01), p. PO-34-PO-34
    Details
    In: Blood Cancer Discovery, American Association for Cancer Research (AACR), Vol. 1, No. 3_Supplement ( 2020-11-01), p. PO-34-PO-34
    Abstract: Recent studies identified germline HAVCR2 (TIM-3) mutations as the specific genetic predisposition to subcutaneous panniculitis-like T-cell lymphoma (SPTCL). However, distinction between HAVCR2-mutated and HAVCR2-wildtype SPTCLs remains elusive. We studied the prevalence of HAVCR2 mutation in a nation-wide cohort of SPTCL and investigated clinical and molecular distinction between HAVCR2-mutated and HAVCR2-wild-type SPTCLs. A multicenter nationwide cohort of 53 SPTCL cases was established; patients were diagnosed at seven Korean institutions between 2003 and 2020. Histologic features were reviewed by experienced hematopathologists and clinical features were retrospectively reviewed. Whole-exome sequencing (WES) and RNA-seq were performed using formalin-fixed, paraffin-embedded (FFPE) samples of 8 patients diagnosed in Seoul National University Hospital (SNUH), with matched non-neoplastic tissue samples from two patients. Direct sequencing of HAVCR2 exon 2 was successfully carried out using FFPE samples from 33 of the remaining 45 patients. Among 41 patients with available HAVCR2 mutation status, 28 (68.3%) were women, and the median age at diagnosis was 30 years (range 11–74). Ten patients (10/40; 25.0%) suffered hemophagocytic syndrome (HPS) or HPS-like systemic illness during the clinical course, and 14 patients (14/40; 35.0%) progressed during the follow-up. Six patients (6/41; 14.6%) died of disease progression or HPS. We found 18 patients (18/41; 43.9%) with HAVCR2 mutation; 15 patients harbored biallelic HAVCR2 Y82C mutation and 3 patients were noted for heterozygous HAVCR2 Y82C mutation. HAVCR2-mutated SPTCLs occurred in younger patients (median age 26.5 versus 37; Mann-Whitney p-value = 0.003), and were more often complicated by HPS or HPS-like systemic illness (10/18 versus 0/22; Fisher's exact p-value & lt; 0.001), compared to HAVCR2-wild-type SPTCLs. Survival analysis using log-rank test revealed that HAVCR2-mutated SPTCLs had shorter progression-free survival, though statistical significance was not achieved (p-value = 0.081) WES results did not show recurrent genetic alteration other than HAVCR2 Y82C in 4 out of 8 patients. Mutations in genes involved in T/NK cell-associated inflammation (PVRL1, PVRL2, TICAM1, GZMA), epigenetic modification (BAZ2A, KMT2C, KMT2D, SETD1A), JAK-STAT signaling (IFNL2, PIAS3), and NF-kB pathway (PDCD11) were observed in individual cases. Gene set enrichment analyses (GSEA) using RNA-seq results showed significant enrichment of pathways involving TNF-alpha signaling via NF-kB (FDR q-value = 0.008), hypoxia (FDR q-value = 0.009), IL6-JAK-STAT3 signaling (FDR q-value = 0.026), apoptosis (FDR q-value = 0.121), and MTORC1 signaling (FDR q-value = 0.188) in HAVCR2-mutated SPTCLs. HAVCR2 Y82C hotspot mutation frequently occurs in Korean patients with SPTCL, which was characterized by unique clinicopathologic features. SPTCL with HAVCR2 Y82C was enriched with distinct cellular pathways, which remains to be further validated. Citation Format: Jiwon Koh, Insoon Jang, Seungchan Mun, Cheol Lee, Hee-Jung Cha, Young Ha Oh, Jin Man Kim, Young Hyeh Ko, Jae Ho Han, Heounjeong Go, Jooryung Huh, Kwangsoo Kim, Yoon Kyung Jeon. Subcutaneous panniculitis-like T-cell lymphoma with HAVCR2 mutation shows unique clinicopathologic features and gene expression profile [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-34.
    Type of Medium: Online Resource
    ISSN: 2643-3230 , 2643-3249
    URL: Article
    DOI: 10.1158/2643-3249.LYMPHOMA20-PO-34
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 8
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    Abstract PD15-08: Window of opportunity trial of neoadjuvant olaparib and durvalumab for triple negative or low ER-positive breast cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. PD15-08-PD15-08
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. PD15-08-PD15-08
    Abstract: Background PARP inhibitors have proven efficacy in breast cancer patients with germline BRCA1 or BRCA2 mutations (gBRCAmt) but also have potential to be effective in cancers with defects in homologous recombination (HR) DNA repair. Moreover, synergy between PARP inhibition and immune checkpoint blockade is expected based on increased mutation burden, neoantigen expression, and immunogenic cell death. Triple negative breast cancer (TNBC) or low estrogen receptor (ER)-positive breast cancers may have diverse defects in HR repair. Methods This is a window of opportunity, serial biopsy trial of olaparib and durvalumab before standard neoadjuvant chemotherapy for TNBC or low ER+ breast cancer (NCT03594396). Patients had clinical stage II/III TNBC or low ER+ HER2- breast cancers where ER was expressed in 10% or lower in tumor cells. Olaparib 300mg bid was given for 4 weeks without rest. One dose of durvalumab 1500mg was given on day 15. Study tumor biopsy and blood sample were taken before the study treatment, after 2 weeks of olaparib before durvalumab, and 2 weeks after durvalumab at the completion of 4 weeks of olaparib. FDG-PET/MRI was taken at baseline, after 2 weeks, after 4 weeks of study treatment, and computed tomography (CT) scan at baseline and after 4 weeks. After the study treatment, standard neoadjuvant chemotherapy with 4 cycles of doxorubicin+cyclophosphamide followed by 4 cycles of docetaxel was given. Primary endpoint was the changes of tumor biology detected by serial tumor biopsy. Secondary endpoints were pathological complete response (pCR) rate, response rate, prediction of early metabolic response by functional HR status, and safety. Functional HR deficiency was assessed by counting RAD51 foci as a marker for HR repair in the baseline tumor tissues before and after 30Gy irradiation to induce DNA damage. Results Fifty-four female patients were enrolled (median age 40 years, range 24-68). ER was negative (TNBC) in 43 patients and low-positive in 11 patients. Clinical stage was II in 25 patients and III in 29 patients, and axillary lymph node involvement was in 47 patients. gBRCAmt was assessed in 53 patients and 16 (30.1%) harbored pathogenic mutations. Functional HR status as measured by RAD51 foci formation was deficient in 27 (50%) patients and proficient in 27 (50%) patients. Functional HR deficiency was related with early metabolic response by FDG-PET after 2 weeks of olaparib (response in 17/27 HR-deficient tumors [63.0%] vs. 7/27 HR-proficient tumors [25.9%] ; p=.006). After 4 weeks of olaparib and durvalumab, HR-deficiency was still related to metabolic response (23/27 vs. 17/27, respectively; p=.062) but HR-proficient tumors also showed metabolic decline. Moreover, HR deficiency was also related with RECIST response measured by CT after 4 weeks (17/27 vs. 9/27; p=.029). As of June 2021, 40 patients completed the neoadjuvant treatment and surgery; among those, 30 achieved pCR (pCR rate 75%). Among 13 patients with gBRCAmt who underwent surgery, 11 achieved pCR (84.6%). Updated results on pCR will be presented. Conclusions Olaparib and durvalumab followed by standard neoadjuvant chemotherapy shows very high pCR rate in TNBC or low ER+ stage II/III breast cancer. Functional HR status as measured by RAD51 foci formation was predictive of early metabolic response to olaparib. Genomic and transcriptomic analyses are underway in the samples before, during, and after olaparib and durvalumab. Citation Format: Seock-Ah Im, Kyung-Hun Lee, Ahrum Min, Daewon Lee, Tae Yong Kim, Han Suk Ryu, Jiwon Koh, Gi-Jeong Cheon, Yoon-Jung Shin, Yujin Kim, Hyeong-Gon Moon, Wonshik Han, Han-Byoel Lee, Morgan Diolaiti, David Quigley, Alan Ashworth, Nariya Cho. Window of opportunity trial of neoadjuvant olaparib and durvalumab for triple negative or low ER-positive breast cancer [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 PD15-08.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-PD15-08
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 9
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    Abstract 4404: E- p -Methoxycinnamoyl-α-l-rhamnopyranosyl ester (MCR) increases Nrf2 stability by inhibiting ubiquitination in HaCaT cells
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4404-4404
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4404-4404
    Abstract: The nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a key regulator of gene expression during oxidative stress and drug detoxification. Thus, identifying Nrf2 activators to protect from possible cell damage is necessary. In this study, we investigated whether E-p-methoxycinnamoyl-α-l-rhamnopyranosyl ester (MCR), a phenylpropanoid isolated from Scrophularia buergeriana, can activate Nrf2 signaling in human keratinocytes (HaCaT). First, we determined the dose- and time-dependent effects of MCR on the expression and activity of Nrf2. The antioxidant response element-luciferase reporter assay and western blot analysis results showed that MCR markedly induced Nrf2 activity and its protein expression, respectively. Further, MCR increased both the mRNA and protein levels of heme-oxygenase-1, one of the Nrf2 target genes, in the cells. Interestingly, we found that Nrf2 stability was remarkably enhanced by MCR. Furthermore, ubiquitin-dependent proteasomal degradation of Nrf2 was significantly reduced by MCR. Thus, MCR might afford skin protection by enhancing Nrf2 stability or by blocking its proteasomal degradation. Citation Format: Jiwon Jeong, Lilik D. Wahyudy, Heejung Yang, Jung-Hwan Kim. E-p-Methoxycinnamoyl-α-l-rhamnopyranosyl ester (MCR) increases Nrf2 stability by inhibiting ubiquitination in HaCaT cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4404.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-4404
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
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    Abstract C066: Update on the phase 1 trial of Nelmastobart in patients with advanced solid tumors
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics Vol. 22, No. 12_Supplement ( 2023-12-01), p. C066-C066
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 12_Supplement ( 2023-12-01), p. C066-C066
    Abstract: Background: Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint that is found to be mutually exclusive with PD-(L)1. BTN1A1 has the potential to broaden the range of immunotherapeutic treatments available for patients who are currently unresponsive to anti-PD-(L)1 therapy. In this phase, 1 clinical trial, the safety and preliminary efficacy of Nelmastobart (hSTC81), a humanized monoclonal antibody targeting BTN1A1, was evaluated in patients with advanced solid tumors. Methods: This is a first-in-human, phase 1, dose-escalation study evaluating Nelmastobart in pts with advanced solid tumors. Primary objectives are to characterize the safety profile and determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Nelmastobart is administered as monotherapy at increasing dose levels of 0.3, 1, 3, 6, 10, and 15 mg/kg on a Q2W schedule. Results: As of June 30, 2023, 45 pts are enrolled at dose levels of 0.3 (n=1), 1 (n=9), 3 (n=10), 6 (n=9), 10 (n=9), and 15 mg/kg (n=8). Of note, 3 pts with ovarian cancer at dose levels of 6 (n=1), 10 (n=1), 15 mg/kg (n=1), and 1 pt with thymic cancer at the dose level of 6 mg/kg (n=1) were enrolled. A maximum administered dose of 15 mg/kg was achieved; no DLTs were observed at any dose level. Focusing on the ovarian/thymic cancer subgroup, 2 pts are ongoing: 1 pt with ovarian cancer (10 mg/kg) and 1 pt with thymic cancer (6 mg/kg). The median duration of therapy was 20 weeks (maximum 33 weeks). Only 1 pt with ovarian cancer (6 mg/kg) reported any treatment-related adverse events (TRAE), including grade 1 headache, nausea, myalgia, and decreased appetite. In the evaluable pts, two confirmed stable diseases are observed in thymic cancer (6 mg/kg) and ovarian cancer (10 mg/kg). The median duration of SD pts is 29 weeks. Preliminary pharmacokinetic (PK) analysis revealed consistent exposure with linear PK. Pharmacodynamic analysis measuring cytokines and cell-based markers is pending and will be shared. Conclusion: Nelmastobart demonstrates excellent tolerability without any DLTs up to the highest administered dose of 15 mg/kg. The available data show promising signs of anti-tumor activity, along with sustained stable disease. Currently, clinical development planning for a phase Ib/II clinical trial is underway, aiming to investigate the optimal therapeutic dose and efficacy of Nelmastobart in multiple types of solid tumors. Citation Format: Stephen Yoo, Soohyeon Lee, Sangjoon Shin, Particia LoRusso, Jiwon Hur, Hyunjin Jung, David S Hong. Update on the phase 1 trial of Nelmastobart in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C066.
    Type of Medium: Online Resource
    ISSN: 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-23-C066
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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