- Email: [email protected]
Vascular Endothelial Growth Factor Receptor Polymorphisms and im Treatment Response in Chronic Myeloid Leukemia Patients
abstracts MO2 18 5
Real-World Effectiveness and Safety of Nivolumab in Special Subgroups of NSCLC pts: A Multicenter-Retrospective Study
Satoru Kitazono1,2, Ryo Morita2, Kyoichi Okishio2, Junichi Shimizu2, Haruhiro Saito2, Hiroshi Sakai2, Young Hak Kim2, Osamu Hataji2, Makiko Yomota2, Keisuke Aoe2, Osamu Kanai2, Toru Kumagai2, Kayoko Kibata2, Hiroaki Tsukamoto2, Satoshi Oizumi2, Keisuke Tomii2, Hiroshi Tanaka2, Keiko Mizuno2, Hirotoshi Hoshiyama3, Kenya Ochi4, Yuichiro Ohe2 1 Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 2Nivolumab Japan Real World Study Group, 3BristolMyers Squibb K.K, 4ONO Pharmaceutical Co., Ltd
MO2 18 6
Real-World Effectiveness and Safety of Nivolumab in NSCLC pts in Japan: A Multicenter-Retrospective Observational Study
Haruhiro Saito1,2, Ryo Morita2, Kyoichi Okishio2, Junichi Shimizu2, Hiroshi Sakai2, Young Hak Kim2, Osamu Hataji2, Makiko Yomota2, Makoto Nishio2, Keisuke Aoe2, Osamu Kanai2, Toru Kumagai2, Kayoko Kibata2, Hiroaki Tsukamoto2, Satoshi Oizumi2, Keisuke Tomii2, Hiroshi Tanaka2, Keiko Mizuno2, Hirotoshi Hoshiyama3, Kenya Ochi4, Yuichiro Ohe2 1 Kanagawa Cancer Center, 2Nivolumab Japan Real World Study Group, 3Bristol-Myers Squibb K.K, 4Ono Pharmaceutical Co., Ltd Background: In December 2015, nivolumab was approved as treatment for previously treated NSCLC irrespective of PD-L1 expression or histology in Japan. There are few reports that include real-world data on large cohorts of patients from Japan. Method: Data from patients who initiated nivolumab treatment from April 1, 2016 to December 31, 2016 were collected at 23 regional medical institutions across Japan. Here we report a retrospective data analysis accessing effectiveness and safety of nivolumab in 901 Japanese NSCLC pts from a multicenter, observational study; CA209-9CR (NCT03273790). Result: Among 901 pts, median age of the pts treated with nivolumab was 67 ys old and proportion of 75 ys or over was 19.8%. Pts with ECOG PS 0 or 1 account for 75.8%, and pts with SQ and adeno histology were 24.5% and 67.7%, respectively. Pts with EGFR mutation account for 12.9%. Median numbers of nivolumab dose was five and nivolumab was most frequently used at 2nd line (46.8%) and followed by at 3rd line (26.5%). Rate of 1 yr overall survival (OS) was 54.3% and, median PFS was 2.1 months and overall ORR was 20.6%. There was no significant difference in effectiveness among histology. Although there was no difference in effectiveness of nivolumab by age, ECOG PS status significantly influence effectiveness of nivolumab. Analysis is ongoing to access various factors that may be associated with the effectiveness of nivolumab. Overall irAE incidence for all grade and grade 3-4 will be reported as well as categorized irAE. Further analysis is planned for safety management of irAEs and prognosis. Conclusion: The effectiveness and safety of nivolumab observed in real-world data from NSCLC patients in Japan was comparable to results observed in clinical trials. ECOG PS status was identified as a factor influencing effectiveness of nivolumab.
MO3 1 1
JAK2 (V617F) positively regulates PD-L1 mRNA expression via STAT3/5 activation in MNP (PV and ET) patients
Sameer Ahmad Guru1, Mamta P Alpana1, Rashid Mir1,2, Imtiyaz A Najar1, Mariyam Zuberi1, Naresh Gupta1, Pramod Lali1, Alpana Saxena1 1 Department of Biochemistry, Maulana Azad Medical College, India, 2University of Tabouk Background:Escalated PD-L1 expression is reported in many cancer types initiating an immune escape mechanism. This led to the development of checkpoint inhibitors against PD-1/PD-L1. However, the mechanisms underlying escalated production of PD-L1 in many cancers is not clear yet.
vi110 | Oral Session : Mini-Oral Abstracts Session
Methods:In this study, we studied PD-L1 mRNA expression levels in concert to JAK2 (V617F) mutation in a group of 72 MPN patients (38 PV and 33 of ET). Clinical and demographical characters were noted carefully. Results:Confirmed MPN patients were screened for JAK2 (V617F) mutation by tetraprimer ARMS-PCR. We next quantified JAK2 (V617F) with ASO-PCR. The patients were also screened for BCR/ABL1 fusion gene transcripts to clarify Ph negative MPN status. The mRNA expression levels of PD-L1, STAT3/5 in all MPN patients were evaluated and it was identified that PD-L1, STAT3 but not STAT5 mRNA levels were significantly high in JAK2 (V617F) patients compared to JAK2 (WT) ones. It was also identified that PD-L1, STAT3/5 mRNA expression was upregulated in MPN patients with more JAK2 (V617F) percentage/allele burden than those MPN patients with less JAK2 (V617F) percentage/allele burden. Finally, we evaluated correlation of JAK2 (V617F) percentage with PD-L1, STAT3/5 mRNA expression levels and discovered that PD-L1 and STAT3 are in strong and direct correlation with JAK2 (V617F) burden while STAT5 was found to be moderately correlated. In addition, we identified strong coexpression of PD-L1 and STAT3 and as expected STAT5 moderately coexisted with PD-L1. Conclusion: In summary,this study shows that increased PD-L1 expression accompanies JAK2 (V617F) mutation. The increased expression of PD-L1 may be caused by excessive activation of STAT3/5 which are regulators of PD-L1. The study finds that PD-L1 expression is mainly mediated by JAK2 (V617F) via STAT3 and thatSTAT5 only plays a minor role.The study supports the concept of using PD-L1/STAT3/5 axes as targets for developing checkpoint inhibitors.
MO3 1 2
Escalated activation ofSTAT3 due to JAK2 V617F activatingmutation causesdownregulation ofPTEN via miRNA 21overexpression
Mamta P Sumi1, Sameer A Guru1, Rashid Mir2, Imtiyaz Najar1, Mariyam Zuberi1, Naresh K Gupta1, Pramod Lali1, Alpana Saxena1 1 Maulana Azad Medical College, India, 2University of Tabouk Background: Mutations in Janus kinase 2 (JAK2) genes are the genetic characteristic of BCR-ABL1-negative myeloproliferative neoplasms (MPN). JAK2 V617F mutation is frequently found in Polycythemia Vera (PV) and Essential Thrombocythemia (ET). We aimed to determine the effect of JAK2 V617F on expression of phosphatase and tensin homolog (PTEN) and its regulator miR-21. Materials and Methods: Seventy two (72) (MPN) patients were screened for JAK2 V617F burden using ASO-PCR. Out of 72 MPN patients, 58 were JAK2 V617F positive and 14 were JAK2 V617F negative. BCR/ABL1 fusion gene transcript screening by multiplex PCR was done to rule out Philadelphia positive MPN. We performed SYBR green based qRT-PCR assay to characterize relative STAT3, PTEN mRNA expression and miR21 expression in 72 MPN patients. Results: The mRNA expression levels of STAT3 and PTEN and mi-21 expression in all MPN patients were evaluated and compared withJAK2 (V617F) and JAK2 (WT) MPN patients. We identified that STAT3 mRNA expression was significantly upregulated in patients with JAK2 (V617F) genotype (mean fold6SD¼2.14 61.2) compared to patients with JAK2 (WT) genotype (mean fold6SD¼1.2360.95). Further, we observed a significantly increased miR 21 expression (mean fold6SD¼2.1860.44) in JAK2 (V617F) patients in comparison to JAK2 (WT) patients (mean fold6SD¼1.7060.49) (p ¼ 0.0003). In addition, we observed that PTEN expression was substantially and significantly downregulated in JAK2 (V617F) patients (mean fold6SD¼ 1.73 6 0.36) compared JAK2 (WT) patients (mean fold6SD¼2.55 6 0.25) (p < 0.0001). Conclusion: In summary, STAT3 activation caused by JAK (V617F) mutation in MPN patients causes overexpression of miR-21 which leads to downregulation of tumour supressor PTEN MPN patients. Thus, our suggests that JAK2 activated STAT3/ miRNA-21 may play a valuable prognostic biomarker for MPN.
MO3 1 4
Vascular Endothelial Growth Factor Receptor Polymorphisms and im Treatment Response in Chronic Myeloid Leukemia Patients
Siti Mariam Ismail1, Ahmad Aizat Abdul Aziz1, Mohd Zaki Husin1, Mohamed Qais Abu Baker1, Mohd Ismail Ibrahim4, Rosline Hasaan2, Sarina Sulong1, Azlan Husin3, Ravindran Ankathil1 1 Human Genome Centre, Universiti Sains Malaysia, Malaysia, 2Department of Haematology, PPSP, Universiti Sains Malaysia, 3Department of Internal Medicine, PPSP,Universiti Sains Malaysia, 4Department of Community Medicine, PPSP,Universiti Sains Malaysia Background: Imatinib mesylate (IM) is the gold standard drug for chronic myeloid leukemia (CML) treatment. However, intrinsic and acquired resistance against IM has become a problem in CML treatment. Vascular endothelial growth factor receptor 2 (VEGFR2) plays a pivotal role in leukemia associated angiogenesis. Its expression is a good predictor of poor survival in CML. Genetic polymorphisms in VEGFR2 result in varied VEGFR2 expression and may lead to inter individual variation in disease progression and outcome to IM therapy. Aim of this study was to investigate the frequencies of VEGFR2 polymorphisms rs1531289 and
Volume 30 | Supplement 6 | October 2019
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Background: In December 2015, nivolumab was approved as treatment for previously treated NSCLC irrespective of PD-L1 expression or histology in Japan. There are few reports that include real-world data on large-scale cohorts of patients with special backgrounds from Japan. Method: Data from patients who initiated nivolumab treatment from April 1, 2016 to December 31, 2016 were collected at 23 regional medical institutions across Japan. Here we report retrospective analysis of all 901 pts data and focus on effectiveness and safety in special subgroups of the Japanese NSCLC patients, from a multicenter, observational study; CA209-9CR (NCT03273790). Result: Patients with EGFR mutations showed significantly shorter PFS as compared to EGFR wild-type patients. Among other special groups, 316 pts with high blood pressure, in which 272 pts was on antihypertensive, showed superior ORR as compared to 585 pts with normal pressure at baseline. Safety analysis showed higher pulmonary toxicity in patients with pulmonary infection at baseline and higher hepatotoxicity in a group of pts infected with hepatitis virus. In this presentation, further analysis on the other subgroups will be presented.
Annals of Oncology
abstracts
Annals of Oncology
MO3 1 6
Geriatric 8 can predict treatment outcomes of elderly patients with de novo AML who received low-dose chemotherapy
Hiroyuki Kobayashi Division of Hematology, Nasu Red Cross Hospital Background: Geriatric assessments (GAs) used to evaluate various aspects in elderly patients have recently been introduced for their usefulness in predicting toxicities of cancer treatments and subsequent patient prognoses. Utilizing GAs to decide on treatment policies has been recommended. However, there are few reports on the relationship between Geriatric 8 (G8), a screening tool for GA, and treatment outcomes of elderly patients with de novo acute myeloid leukemia (AML) who received low-dose chemotherapy (LDC). Patients and Methods: We reviewed 47 patients aged70 years who were newly diagnosed with de novo AML (except for acute promyelocytic leukemia) and received LDC as an initial treatment at our hospital between April 2012 and June 2018. We divided them into two groups (high: N ¼ 11, low: N ¼ 36) according to G8 scores (cutoff: 14 points) at the time of diagnosis and retrospectively analyzed the differences in clinical features and treatment outcomes. Results: Statistically significant differences in age (median, 73 vs. 79 years, p ¼ 0.009) were observed between the two groups. The proportions of sex, median white blood cell and bone marrow blast counts, and percentages of patients with unfavorable cytogenetic abnormalities did not differ significantly between groups. The most frequent initial LDC in both groups was low-dose cytarabine combined with acrarubicine. The complete remission rate and overall survival at two years were significantly higher in the G8 high-score group than those in the low-score group (72.7% vs. 19.4%; p ¼ 0.002 and 55.6% vs. 11.0%; p < 0.001), respectively. Early death from fatal infections, bleeding, and disease progression were frequently observed in the G8 low-score group (0.0% vs. 11.1%). Conclusion: Our data suggest that G8 scores can predict treatment outcomes in elderly patients with de novo AML who received LDC.
MO3 2 1
Correlation between Ghrelin and gastrointestinal stromal tumors/Study on mechanism of Ghrelin regulating GISTs growth
Changzhen Zhu Beijing Tsinghua Changgeng Hospital, China Objective: Treatment of gastrointestinal stromal tumors(GISTs) is facing a bottleneck. Ghrelin is mainly produced by stomach fundus, and can promote proliferation of malignant tumors. Ghrelin may provide new ideas for GISTs diagnosis and treatment. 1) whether Ghrelin can be useful for GISTs diagnosis and prognosis. 2) Ghrelin mechanism GISTs growth regulation. Method: 1) Collect serum of normal people, GISTs and patients with digestive tract malignant tumor and determine the level of ghrelin in serum. GISTs and paracancerous normal tissues were collected and ghrelin and its receptor were measured. We correlated ghrelin with clinicopathological data, analyzed the correlation between ghrelin and GISTs and its role in nutritional risk assessment. 2) The mechanism of ghrelin regulating the growth of GISTs was preliminarily explored by cell slicing, cell proliferation assay and Western blotting. Result: 1) Serum Ghrelin can be used as a reference index for the existence of GISTs, but no specificity. Prognosis can not be predicted by serum Ghrelin. 2) Ghrelin of GISTs can be used as a reference index for GISTs malignant degree and recurrence risk. 3) GISTs secrete Ghrelin through autocrine and paracrine. 4) Ghrelin and its receptor antagonists can induce ghrelin receptor expression. 5) Ghrelin participates in the regulation of GISTs growth through multiple pathways. 6) Ghrelin can be used as a useful reference index for judging nutritional risk.
Volume 30 | Supplement 6 | October 2019
Conclusion: Ghrelin participates in the growth regulation of GISTs and has certain reference significance for judging the malignant degree, recurrence risk and perioperative nutritional risk of patients with gastrointestinal malignancies.
MO3 2 2
Clinical outcome of salvage chemotherapy after oxaliplatin based chemotherapy for metastatic small bowel adenocarcinoma
Yoshitaka Homma1, Hidekazu Hirano2, Hirokazu Shoji2, Natsuko Okita2, Satoru Iwasa2, Atsuo Takashima2, Ken Kato2, Narikazu Boku1 1 Head and Neck Medical Oncology Division, Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 2Gastrointestinal Medical Oncology Division, National Cancer Center Hospital Background: Although palliative chemotherapy (CTx) for metastatic small bowel adenocarcinoma (mSBA) has not been established, fluoropyrimidine plus oxaliplatin (FOx) is globally accepted as a standard CTx based on several studies. While CTx for colorectal cancer has been recommended in NCCN guidelines, limited efficacy of irinotecan (IRI) and panitumumab for mSBA had also been shown in western countries. Thus, there has been no salvage line chemotherapy (SLC) which can be recommended for mSBA after failure to FOx. The aim of this study was to provide the information of clinical outcomes of SLC for mSBA after failure of FOx. Methods: mSBA patients (pts) who received SLC after failure of FOx from 2010 to 2019 in our institute were retrospectively analyzed. Pts who received 1st line CTx other than FOx, ongoing FOx, or with insufficient follow-up were excluded. Results: Of 59 mSBA pts, eligible 33 were extracted from our database. Age (median): 58 year-old, PS (0/1/>¼2): 3/21/9, primary site (duodenum/jejunum and ileum): 13/ 20, stage (IV/recurrence): 23/10. Metastatic sites were peritoneum in 25 (75.8%) pts, and liver in 12 (36.4%). Twenty-two (66.7%) pts received SLC, pts with good PS (0-1) tended to receive SLC. As 2nd line CTx, 16 of 22 pts (72.7%) received IRI-based CTx and gemcitabine (GEM) in 3. Eight of 22 pts received 3rd line CTx; nab-paclitaxel (offlabel use for APC-wild type) in 4, and GEM in 2. MST in all pts was 4.5 months, which was longer in pts treated with SLC than those with best supportive care (5.7 vs 1.7 months, p < 0.001). Multivariate analyses revealed duodenum primary and no SLC were independently related to poor prognosis. In 22 pts who received SLC, median PFS, ORR, and DCR were 2.3 months, 0%, and 31.8%, respectively. In univariate analyses, no prognostic factor was shown for PFS. Conclusion: Limited efficacy of SLC for mSBA was shown also in Japanese population. This is very important baseline data to lead to the future drug development.
MO3 2 3
Study on mid-term effectiveness of community based colorectal cancer screening program
Weixing Dai Fudan university shanghai cancer center, China Background: To date, limited incidence or mortality reducing impact were reported in Asian populations. The aim of this study was to reveal the mid-term effectiveness of colorectal cancer screening by following population in the communities in Shanghai, China. Methods: Organized Colorectal Cancer Screening initiated in the screened community since the year of 2008 and repeated yearly. Questionnaire based risk assessment and iFOBT were the two screening approaches used in this program. The data of incidence and mortality by the end of the year 2015 in the screened and control community were based on the cancer registry data, death registry data and the population data provided by centers for disease control. The last follow-up time for CRC patients was set at the end of the year 2017. Kaplan-Meier estimator was utilized to conduct survival analysis. Annual Percent Change was used for incidence and mortality trends analysis. Results: In 2008, a total of 20,936 residents covering 25.4% of target population in the screened community participated in colorectal cancer screening. Between 2008 to 2015, A total of 670 adenomas were detected, and 80 CRC cases were screened out successfully. Between 2008 to 2015, a total of 80 CRC cases were screened out successfully. Overall CRC incidence in the screened community (APC -8.41, P < 0.05) decreased significantly during the period of 2008-2015. Specifically, notably decrease in incidence was observed in colon and female CRC. While in the control community, the CRC incidence maintained a slight increasing trend with no significance (APC 3.2, P < 0.05). Upon mortality trend, no significant change was observed in the screened community (APC -1.32, P > 0.05), but a distinct increasing trend in the control community (APC 32.43, P < 0.05). Conclusion: Colorectal cancer screening was significantly associated with improved overall survival, and also contributed to the reducing colorectal cancer incidence.
doi:10.1093/annonc/mdz338 | vi111
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rs2305948 in Malaysian CML patients and to determine the impact of these SNPs on IM treatment response in these CML patients. Methods: DNA extracted from 230 CML patients (121 IM resistant and 109 IM good response) were genotyped using restriction fragment length polymorphism analysis and genotypes were categorized into homozygous wildtype, heterozygous and homozygous variants. The difference in genotype frequencies of the two SNPs, between the two groups of CML patients were compared using x2 test and the association between genotypes and treatment response was assessed using logistic regression analysis and deriving ORs with 95% CI. Results: The SNP rs1531289 did not show any significant association with IM resistance. For rs2305948, the heterozygous variant genotype (CT) and variant allele (T) showed significant association with IM resistance (OR, 2.38; CI,1.33-4.25, p ¼ 0.003 and OR,1.48; CI, 1.02-2.14,p¼0.039 respectively). Haplotype analysis of the two SNPs did not show any association with treatment response. Conclusion: VEGFR2 polymorphism rs2305948 which is associated with cytogenetic response and development of resistance to IM therapy might be a potential prognostic predictor of IM treatment response in CML patients. This study was financially supported by Research University Grant of Universiti Sains Malaysia, 2017.
Real-World Effectiveness and Safety of Nivolumab in Special Subgroups of NSCLC pts: A Multicenter-Retrospective Study
Satoru Kitazono1,2, Ryo Morita2, Kyoichi Okishio2, Junichi Shimizu2, Haruhiro Saito2, Hiroshi Sakai2, Young Hak Kim2, Osamu Hataji2, Makiko Yomota2, Keisuke Aoe2, Osamu Kanai2, Toru Kumagai2, Kayoko Kibata2, Hiroaki Tsukamoto2, Satoshi Oizumi2, Keisuke Tomii2, Hiroshi Tanaka2, Keiko Mizuno2, Hirotoshi Hoshiyama3, Kenya Ochi4, Yuichiro Ohe2 1 Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 2Nivolumab Japan Real World Study Group, 3BristolMyers Squibb K.K, 4ONO Pharmaceutical Co., Ltd
MO2 18 6
Real-World Effectiveness and Safety of Nivolumab in NSCLC pts in Japan: A Multicenter-Retrospective Observational Study
Haruhiro Saito1,2, Ryo Morita2, Kyoichi Okishio2, Junichi Shimizu2, Hiroshi Sakai2, Young Hak Kim2, Osamu Hataji2, Makiko Yomota2, Makoto Nishio2, Keisuke Aoe2, Osamu Kanai2, Toru Kumagai2, Kayoko Kibata2, Hiroaki Tsukamoto2, Satoshi Oizumi2, Keisuke Tomii2, Hiroshi Tanaka2, Keiko Mizuno2, Hirotoshi Hoshiyama3, Kenya Ochi4, Yuichiro Ohe2 1 Kanagawa Cancer Center, 2Nivolumab Japan Real World Study Group, 3Bristol-Myers Squibb K.K, 4Ono Pharmaceutical Co., Ltd Background: In December 2015, nivolumab was approved as treatment for previously treated NSCLC irrespective of PD-L1 expression or histology in Japan. There are few reports that include real-world data on large cohorts of patients from Japan. Method: Data from patients who initiated nivolumab treatment from April 1, 2016 to December 31, 2016 were collected at 23 regional medical institutions across Japan. Here we report a retrospective data analysis accessing effectiveness and safety of nivolumab in 901 Japanese NSCLC pts from a multicenter, observational study; CA209-9CR (NCT03273790). Result: Among 901 pts, median age of the pts treated with nivolumab was 67 ys old and proportion of 75 ys or over was 19.8%. Pts with ECOG PS 0 or 1 account for 75.8%, and pts with SQ and adeno histology were 24.5% and 67.7%, respectively. Pts with EGFR mutation account for 12.9%. Median numbers of nivolumab dose was five and nivolumab was most frequently used at 2nd line (46.8%) and followed by at 3rd line (26.5%). Rate of 1 yr overall survival (OS) was 54.3% and, median PFS was 2.1 months and overall ORR was 20.6%. There was no significant difference in effectiveness among histology. Although there was no difference in effectiveness of nivolumab by age, ECOG PS status significantly influence effectiveness of nivolumab. Analysis is ongoing to access various factors that may be associated with the effectiveness of nivolumab. Overall irAE incidence for all grade and grade 3-4 will be reported as well as categorized irAE. Further analysis is planned for safety management of irAEs and prognosis. Conclusion: The effectiveness and safety of nivolumab observed in real-world data from NSCLC patients in Japan was comparable to results observed in clinical trials. ECOG PS status was identified as a factor influencing effectiveness of nivolumab.
MO3 1 1
JAK2 (V617F) positively regulates PD-L1 mRNA expression via STAT3/5 activation in MNP (PV and ET) patients
Sameer Ahmad Guru1, Mamta P Alpana1, Rashid Mir1,2, Imtiyaz A Najar1, Mariyam Zuberi1, Naresh Gupta1, Pramod Lali1, Alpana Saxena1 1 Department of Biochemistry, Maulana Azad Medical College, India, 2University of Tabouk Background:Escalated PD-L1 expression is reported in many cancer types initiating an immune escape mechanism. This led to the development of checkpoint inhibitors against PD-1/PD-L1. However, the mechanisms underlying escalated production of PD-L1 in many cancers is not clear yet.
vi110 | Oral Session : Mini-Oral Abstracts Session
Methods:In this study, we studied PD-L1 mRNA expression levels in concert to JAK2 (V617F) mutation in a group of 72 MPN patients (38 PV and 33 of ET). Clinical and demographical characters were noted carefully. Results:Confirmed MPN patients were screened for JAK2 (V617F) mutation by tetraprimer ARMS-PCR. We next quantified JAK2 (V617F) with ASO-PCR. The patients were also screened for BCR/ABL1 fusion gene transcripts to clarify Ph negative MPN status. The mRNA expression levels of PD-L1, STAT3/5 in all MPN patients were evaluated and it was identified that PD-L1, STAT3 but not STAT5 mRNA levels were significantly high in JAK2 (V617F) patients compared to JAK2 (WT) ones. It was also identified that PD-L1, STAT3/5 mRNA expression was upregulated in MPN patients with more JAK2 (V617F) percentage/allele burden than those MPN patients with less JAK2 (V617F) percentage/allele burden. Finally, we evaluated correlation of JAK2 (V617F) percentage with PD-L1, STAT3/5 mRNA expression levels and discovered that PD-L1 and STAT3 are in strong and direct correlation with JAK2 (V617F) burden while STAT5 was found to be moderately correlated. In addition, we identified strong coexpression of PD-L1 and STAT3 and as expected STAT5 moderately coexisted with PD-L1. Conclusion: In summary,this study shows that increased PD-L1 expression accompanies JAK2 (V617F) mutation. The increased expression of PD-L1 may be caused by excessive activation of STAT3/5 which are regulators of PD-L1. The study finds that PD-L1 expression is mainly mediated by JAK2 (V617F) via STAT3 and thatSTAT5 only plays a minor role.The study supports the concept of using PD-L1/STAT3/5 axes as targets for developing checkpoint inhibitors.
MO3 1 2
Escalated activation ofSTAT3 due to JAK2 V617F activatingmutation causesdownregulation ofPTEN via miRNA 21overexpression
Mamta P Sumi1, Sameer A Guru1, Rashid Mir2, Imtiyaz Najar1, Mariyam Zuberi1, Naresh K Gupta1, Pramod Lali1, Alpana Saxena1 1 Maulana Azad Medical College, India, 2University of Tabouk Background: Mutations in Janus kinase 2 (JAK2) genes are the genetic characteristic of BCR-ABL1-negative myeloproliferative neoplasms (MPN). JAK2 V617F mutation is frequently found in Polycythemia Vera (PV) and Essential Thrombocythemia (ET). We aimed to determine the effect of JAK2 V617F on expression of phosphatase and tensin homolog (PTEN) and its regulator miR-21. Materials and Methods: Seventy two (72) (MPN) patients were screened for JAK2 V617F burden using ASO-PCR. Out of 72 MPN patients, 58 were JAK2 V617F positive and 14 were JAK2 V617F negative. BCR/ABL1 fusion gene transcript screening by multiplex PCR was done to rule out Philadelphia positive MPN. We performed SYBR green based qRT-PCR assay to characterize relative STAT3, PTEN mRNA expression and miR21 expression in 72 MPN patients. Results: The mRNA expression levels of STAT3 and PTEN and mi-21 expression in all MPN patients were evaluated and compared withJAK2 (V617F) and JAK2 (WT) MPN patients. We identified that STAT3 mRNA expression was significantly upregulated in patients with JAK2 (V617F) genotype (mean fold6SD¼2.14 61.2) compared to patients with JAK2 (WT) genotype (mean fold6SD¼1.2360.95). Further, we observed a significantly increased miR 21 expression (mean fold6SD¼2.1860.44) in JAK2 (V617F) patients in comparison to JAK2 (WT) patients (mean fold6SD¼1.7060.49) (p ¼ 0.0003). In addition, we observed that PTEN expression was substantially and significantly downregulated in JAK2 (V617F) patients (mean fold6SD¼ 1.73 6 0.36) compared JAK2 (WT) patients (mean fold6SD¼2.55 6 0.25) (p < 0.0001). Conclusion: In summary, STAT3 activation caused by JAK (V617F) mutation in MPN patients causes overexpression of miR-21 which leads to downregulation of tumour supressor PTEN MPN patients. Thus, our suggests that JAK2 activated STAT3/ miRNA-21 may play a valuable prognostic biomarker for MPN.
MO3 1 4
Vascular Endothelial Growth Factor Receptor Polymorphisms and im Treatment Response in Chronic Myeloid Leukemia Patients
Siti Mariam Ismail1, Ahmad Aizat Abdul Aziz1, Mohd Zaki Husin1, Mohamed Qais Abu Baker1, Mohd Ismail Ibrahim4, Rosline Hasaan2, Sarina Sulong1, Azlan Husin3, Ravindran Ankathil1 1 Human Genome Centre, Universiti Sains Malaysia, Malaysia, 2Department of Haematology, PPSP, Universiti Sains Malaysia, 3Department of Internal Medicine, PPSP,Universiti Sains Malaysia, 4Department of Community Medicine, PPSP,Universiti Sains Malaysia Background: Imatinib mesylate (IM) is the gold standard drug for chronic myeloid leukemia (CML) treatment. However, intrinsic and acquired resistance against IM has become a problem in CML treatment. Vascular endothelial growth factor receptor 2 (VEGFR2) plays a pivotal role in leukemia associated angiogenesis. Its expression is a good predictor of poor survival in CML. Genetic polymorphisms in VEGFR2 result in varied VEGFR2 expression and may lead to inter individual variation in disease progression and outcome to IM therapy. Aim of this study was to investigate the frequencies of VEGFR2 polymorphisms rs1531289 and
Volume 30 | Supplement 6 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz338.088/5583018 by guest on 21 October 2019
Background: In December 2015, nivolumab was approved as treatment for previously treated NSCLC irrespective of PD-L1 expression or histology in Japan. There are few reports that include real-world data on large-scale cohorts of patients with special backgrounds from Japan. Method: Data from patients who initiated nivolumab treatment from April 1, 2016 to December 31, 2016 were collected at 23 regional medical institutions across Japan. Here we report retrospective analysis of all 901 pts data and focus on effectiveness and safety in special subgroups of the Japanese NSCLC patients, from a multicenter, observational study; CA209-9CR (NCT03273790). Result: Patients with EGFR mutations showed significantly shorter PFS as compared to EGFR wild-type patients. Among other special groups, 316 pts with high blood pressure, in which 272 pts was on antihypertensive, showed superior ORR as compared to 585 pts with normal pressure at baseline. Safety analysis showed higher pulmonary toxicity in patients with pulmonary infection at baseline and higher hepatotoxicity in a group of pts infected with hepatitis virus. In this presentation, further analysis on the other subgroups will be presented.
Annals of Oncology
abstracts
Annals of Oncology
MO3 1 6
Geriatric 8 can predict treatment outcomes of elderly patients with de novo AML who received low-dose chemotherapy
Hiroyuki Kobayashi Division of Hematology, Nasu Red Cross Hospital Background: Geriatric assessments (GAs) used to evaluate various aspects in elderly patients have recently been introduced for their usefulness in predicting toxicities of cancer treatments and subsequent patient prognoses. Utilizing GAs to decide on treatment policies has been recommended. However, there are few reports on the relationship between Geriatric 8 (G8), a screening tool for GA, and treatment outcomes of elderly patients with de novo acute myeloid leukemia (AML) who received low-dose chemotherapy (LDC). Patients and Methods: We reviewed 47 patients aged70 years who were newly diagnosed with de novo AML (except for acute promyelocytic leukemia) and received LDC as an initial treatment at our hospital between April 2012 and June 2018. We divided them into two groups (high: N ¼ 11, low: N ¼ 36) according to G8 scores (cutoff: 14 points) at the time of diagnosis and retrospectively analyzed the differences in clinical features and treatment outcomes. Results: Statistically significant differences in age (median, 73 vs. 79 years, p ¼ 0.009) were observed between the two groups. The proportions of sex, median white blood cell and bone marrow blast counts, and percentages of patients with unfavorable cytogenetic abnormalities did not differ significantly between groups. The most frequent initial LDC in both groups was low-dose cytarabine combined with acrarubicine. The complete remission rate and overall survival at two years were significantly higher in the G8 high-score group than those in the low-score group (72.7% vs. 19.4%; p ¼ 0.002 and 55.6% vs. 11.0%; p < 0.001), respectively. Early death from fatal infections, bleeding, and disease progression were frequently observed in the G8 low-score group (0.0% vs. 11.1%). Conclusion: Our data suggest that G8 scores can predict treatment outcomes in elderly patients with de novo AML who received LDC.
MO3 2 1
Correlation between Ghrelin and gastrointestinal stromal tumors/Study on mechanism of Ghrelin regulating GISTs growth
Changzhen Zhu Beijing Tsinghua Changgeng Hospital, China Objective: Treatment of gastrointestinal stromal tumors(GISTs) is facing a bottleneck. Ghrelin is mainly produced by stomach fundus, and can promote proliferation of malignant tumors. Ghrelin may provide new ideas for GISTs diagnosis and treatment. 1) whether Ghrelin can be useful for GISTs diagnosis and prognosis. 2) Ghrelin mechanism GISTs growth regulation. Method: 1) Collect serum of normal people, GISTs and patients with digestive tract malignant tumor and determine the level of ghrelin in serum. GISTs and paracancerous normal tissues were collected and ghrelin and its receptor were measured. We correlated ghrelin with clinicopathological data, analyzed the correlation between ghrelin and GISTs and its role in nutritional risk assessment. 2) The mechanism of ghrelin regulating the growth of GISTs was preliminarily explored by cell slicing, cell proliferation assay and Western blotting. Result: 1) Serum Ghrelin can be used as a reference index for the existence of GISTs, but no specificity. Prognosis can not be predicted by serum Ghrelin. 2) Ghrelin of GISTs can be used as a reference index for GISTs malignant degree and recurrence risk. 3) GISTs secrete Ghrelin through autocrine and paracrine. 4) Ghrelin and its receptor antagonists can induce ghrelin receptor expression. 5) Ghrelin participates in the regulation of GISTs growth through multiple pathways. 6) Ghrelin can be used as a useful reference index for judging nutritional risk.
Volume 30 | Supplement 6 | October 2019
Conclusion: Ghrelin participates in the growth regulation of GISTs and has certain reference significance for judging the malignant degree, recurrence risk and perioperative nutritional risk of patients with gastrointestinal malignancies.
MO3 2 2
Clinical outcome of salvage chemotherapy after oxaliplatin based chemotherapy for metastatic small bowel adenocarcinoma
Yoshitaka Homma1, Hidekazu Hirano2, Hirokazu Shoji2, Natsuko Okita2, Satoru Iwasa2, Atsuo Takashima2, Ken Kato2, Narikazu Boku1 1 Head and Neck Medical Oncology Division, Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 2Gastrointestinal Medical Oncology Division, National Cancer Center Hospital Background: Although palliative chemotherapy (CTx) for metastatic small bowel adenocarcinoma (mSBA) has not been established, fluoropyrimidine plus oxaliplatin (FOx) is globally accepted as a standard CTx based on several studies. While CTx for colorectal cancer has been recommended in NCCN guidelines, limited efficacy of irinotecan (IRI) and panitumumab for mSBA had also been shown in western countries. Thus, there has been no salvage line chemotherapy (SLC) which can be recommended for mSBA after failure to FOx. The aim of this study was to provide the information of clinical outcomes of SLC for mSBA after failure of FOx. Methods: mSBA patients (pts) who received SLC after failure of FOx from 2010 to 2019 in our institute were retrospectively analyzed. Pts who received 1st line CTx other than FOx, ongoing FOx, or with insufficient follow-up were excluded. Results: Of 59 mSBA pts, eligible 33 were extracted from our database. Age (median): 58 year-old, PS (0/1/>¼2): 3/21/9, primary site (duodenum/jejunum and ileum): 13/ 20, stage (IV/recurrence): 23/10. Metastatic sites were peritoneum in 25 (75.8%) pts, and liver in 12 (36.4%). Twenty-two (66.7%) pts received SLC, pts with good PS (0-1) tended to receive SLC. As 2nd line CTx, 16 of 22 pts (72.7%) received IRI-based CTx and gemcitabine (GEM) in 3. Eight of 22 pts received 3rd line CTx; nab-paclitaxel (offlabel use for APC-wild type) in 4, and GEM in 2. MST in all pts was 4.5 months, which was longer in pts treated with SLC than those with best supportive care (5.7 vs 1.7 months, p < 0.001). Multivariate analyses revealed duodenum primary and no SLC were independently related to poor prognosis. In 22 pts who received SLC, median PFS, ORR, and DCR were 2.3 months, 0%, and 31.8%, respectively. In univariate analyses, no prognostic factor was shown for PFS. Conclusion: Limited efficacy of SLC for mSBA was shown also in Japanese population. This is very important baseline data to lead to the future drug development.
MO3 2 3
Study on mid-term effectiveness of community based colorectal cancer screening program
Weixing Dai Fudan university shanghai cancer center, China Background: To date, limited incidence or mortality reducing impact were reported in Asian populations. The aim of this study was to reveal the mid-term effectiveness of colorectal cancer screening by following population in the communities in Shanghai, China. Methods: Organized Colorectal Cancer Screening initiated in the screened community since the year of 2008 and repeated yearly. Questionnaire based risk assessment and iFOBT were the two screening approaches used in this program. The data of incidence and mortality by the end of the year 2015 in the screened and control community were based on the cancer registry data, death registry data and the population data provided by centers for disease control. The last follow-up time for CRC patients was set at the end of the year 2017. Kaplan-Meier estimator was utilized to conduct survival analysis. Annual Percent Change was used for incidence and mortality trends analysis. Results: In 2008, a total of 20,936 residents covering 25.4% of target population in the screened community participated in colorectal cancer screening. Between 2008 to 2015, A total of 670 adenomas were detected, and 80 CRC cases were screened out successfully. Between 2008 to 2015, a total of 80 CRC cases were screened out successfully. Overall CRC incidence in the screened community (APC -8.41, P < 0.05) decreased significantly during the period of 2008-2015. Specifically, notably decrease in incidence was observed in colon and female CRC. While in the control community, the CRC incidence maintained a slight increasing trend with no significance (APC 3.2, P < 0.05). Upon mortality trend, no significant change was observed in the screened community (APC -1.32, P > 0.05), but a distinct increasing trend in the control community (APC 32.43, P < 0.05). Conclusion: Colorectal cancer screening was significantly associated with improved overall survival, and also contributed to the reducing colorectal cancer incidence.
doi:10.1093/annonc/mdz338 | vi111
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rs2305948 in Malaysian CML patients and to determine the impact of these SNPs on IM treatment response in these CML patients. Methods: DNA extracted from 230 CML patients (121 IM resistant and 109 IM good response) were genotyped using restriction fragment length polymorphism analysis and genotypes were categorized into homozygous wildtype, heterozygous and homozygous variants. The difference in genotype frequencies of the two SNPs, between the two groups of CML patients were compared using x2 test and the association between genotypes and treatment response was assessed using logistic regression analysis and deriving ORs with 95% CI. Results: The SNP rs1531289 did not show any significant association with IM resistance. For rs2305948, the heterozygous variant genotype (CT) and variant allele (T) showed significant association with IM resistance (OR, 2.38; CI,1.33-4.25, p ¼ 0.003 and OR,1.48; CI, 1.02-2.14,p¼0.039 respectively). Haplotype analysis of the two SNPs did not show any association with treatment response. Conclusion: VEGFR2 polymorphism rs2305948 which is associated with cytogenetic response and development of resistance to IM therapy might be a potential prognostic predictor of IM treatment response in CML patients. This study was financially supported by Research University Grant of Universiti Sains Malaysia, 2017.