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Tumor mutational burden (TMB) is a genomic biomarker associated with the benefits of immune checkpoint inhibitors (ICIs). Detection of elevated blood TMB (bTMB) in circulating tumor DNA represents a compelling noninvasive approach. However, the validity and utility of this emerging biomarker across cancer types has not been established. To better understand bTMB landscape, a preliminary analysis of bTMB was performed in a large clinical cohort and MONSTAR-SCREEN. There was higher agreement between TMB and bTMB in samples with higher levels of plasma tumor fraction (TF). Among patients with bTMB-high treated with ICIs, there was a trend toward a higher response rate and longer progression-free survival, which was more pronounced among patients with TF≥10%. Our findings suggest elevated bTMB is correlated with elevated TMB and represents a pragmatic biomarker for assessing ICIs benefits. The utility of this biomarker is likely to be associated with high TF levels, informing future prospective investigations.

213 Background: Preclinical and clinical data from various types of cancer show that the gut microbiome can affect the outcome of treatments with immune checkpoint inhibitors or cytotoxic chemotherapies. However, the relationship between the microbiome and treatment outcomes in prostate cancer has remained unclear. Here, we present a comprehensive analysis of the relationship between the gut microbiome and treatment outcomes from a nationwide genome screening project (MONSTAR-SCREEN 1) in patients with metastatic castration-sensitive and -resistant prostate cancer (mCSPC and mCRPC). Methods: We performed 16S rRNA gene sequencing of fecal DNA from 73 mCSPC and 83 mCRPC patients before treatment. The microbiome data were compared using the Wilcoxon-Mann-Whitney test or Fisher’s exact test. Survival status and therapeutic efficacy of ADT based treatment were prospectively collected and estimated using the Kaplan-Meier method, and the log-rank test was used to compare survival in different strata. Results: Fecal samples from mCRPC had more Klebsiella and Enterobacteriaceae than those from mCSPC, whereas mCSPC had more Akkermansia and Bifidobacterium compared to mCRPC. Prior and concurrent usage of anti-biotics did not affect diversity of the amplicon sequence variants (ASVs), KEGG orthology and metabolism pathway representation. Anti-biotics also did not influence time to treatment failure (TTF) in mCRPC (HR:0.81, 95%CI:0.36–1.78) and mCSPC (HR:1.35, 95%CI:0.55–3.34). mCRPC had more diverse KEGG orthology compared to mCSPC ( p=0.0009), however, no statistical differences were observed in the ASV ( p=0.77) and metabolism pathway representation ( p=0.35) between mCRPC and mCSPC. High ASV tended to be associated with longer TTF rather than low ASV in both mCRPC (Adjusted HR:0.63, 95%CI:0.34–1.10) and mCSPC (Adjusted HR:0.66, 95%CI:0.31–1.40). mCRPC patients with high AVS also showed significant longer PSA-progression free survival than patients with low ASV (HR:053, 95%CI:0.28–0.99). Conclusions: This investigation revealed significant differences in the microbiome status of mCRPC compared to mCSPC. These differences and diversity might influence the outcomes of ADT based treatment in prostate cancer.

733 Background: MONSTAR-SCREEN prospectively assessed the gut microbiota of 2000 patients (pts) with advanced solid cancer at 31 Japanese institutions. Here, we report the interim analysis results of the correlation between gut microbiota and the efficacy of first-line chemotherapy in pts with unresectable pancreatic cancer (PC) and bile tract cancer (BTC). Methods: We analyzed unresectable 205 PC and 83 BTC pts with clinical data as data cut-off on April 30, 2021, and 16S ribosome analysis results of stool samples. Among PC pts, 133 and 40 were treated with GnP (gemcitabine (GEM) plus nab-paclitaxel) and FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), respectively. Among BTC pts, 32 and 33 were treated with GC (GEM plus cisplatin) and GCS (GEM, cisplatin, plus S-1), respectively. Pts with an above-median overall survival (OS) were defined as long-term survivors (LTS), and those with below-median OS and OS events were defined as short-term survivors (STS). We compared the alpha diversity index (ADI) of LTS and STS, and identified potential microbial biomarkers of LTS, STS, responders, and non-responders to first-line chemotherapy according to RECIST version 1.1, by linear discriminant analysis effect size (LEfSe). In each cohort, the top three microbiota with linear discriminant analysis scores of ≥ 3.0 were considered significant. Results: The median OS of PC and BTC pts was 13.5 and 15.9 months, respectively. In PC pts, no significant difference was noted in the ADI between LTS (n=20) and STS (n=40). In BTC pts, the ADI of LTS (n=10) was significantly higher than that of STS (n=20) in the Shannon index. LEfSe analysis in PC pts revealed that Burkholderiales and Sutterellaceae were predominant in LTS, while Lactobacillaceae was, in STS. In PC pts, Brachyspiraceae and Erysipelotrichales were predominant in responders (n=67), while Enterococcaceae and Lactobacillaceae were, in non-responders (n=137). In BTC pts, Peptostreptococcaceae, Fusobacteriaceae, and Clostridiaceae in LTS; Cardiobacteriaceae, Prevotellaceae, and Actinobacteriota in responders (n=24); and Bacilli in non-responders (n=59) were overrepresented. Conclusions: This interim analysis identified potential biomarkers of the gut microbiota that may contribute to the prognosis and efficacy of chemotherapy in pts with unresectable PC and BTC. The results of this analysis will be validated in the primary analysis.

Background A previous phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab for patients with heavily pretreated metastatic colorectal cancer (mCRC) showed promising activity with an acceptable toxicity profile. This retrospective study aimed to investigate the safety and efficacy of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC in clinical settings. Methods Records of patients with mCRC refractory to standard therapies who initiated trifluridine/tipiracil plus bevacizumab from January 2016 to March 2018 or trifluridine/tipiracil monotherapy from June 2014 to December 2015 were retrospectively reviewed at our institution. Results Totally, 60 patients received trifluridine/tipiracil plus bevacizumab and 66 received trifluridine/tipiracil monotherapy. All patients had previously received standard chemotherapy. Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 2.3–5.1] in the trifluridine/tipiracil plus bevacizumab group and 2.2 months (95% CI, 1.8–2.6) in the trifluridine/tipiracil monotherapy group [hazards ratio (HR) 0.69; 95% CI 0.48–0.99]. PFS rate at 16 weeks was 46.6% for the trifluridine/tipiracil plus bevacizumab group and 33.9% for the trifluridine/tipiracil monotherapy group. Although a relatively higher incidence of grade ≥ 3 neutropenia was observed in the trifluridine/tipiracil plus bevacizumab group than that in the other group (50.0% vs. 40.9%, p = 0.371), the incidence of febrile neutropenia was not high (3.3% vs. 7.8%, p = 0.444). Conclusions In real-world settings, trifluridine/tipiracil plus bevacizumab prolonged PFS and helped achieve higher 16-week PFS rate compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC with manageable toxicities. Trial registration Retrospectively registered.

152 Background: Circulating tumor DNA in plasma (ctDNA) is an emerging resource for detecting genomic alterations in various cancers. However, the characteristics and clinical utility of ctDNA are not fully elucidated, especially in patients with genitourinary (GU) cancers. Methods: In April 2019, SCRUM-Japan started the MONSTAR-SCREEN project, which evaluates the ctDNA from patients with various advanced solid tumors. We collected plasma and tumor samples from patients with advanced prostate cancer (PC), urothelial carcinoma (UC), and renal cell carcinoma (RCC). Plasma ctDNA and tissue genomic DNA were analyzed using NGS-based cell-free DNA assay, a modified version of FoundationOne Liquid (F1L) including blood tumor mutational burden (TMB) analysis, and tissue-based panel, FoundationOne CDx (F1CDx), respectively. Success rate of ctDNA was defined as the percentage of patients whose sample quality control status was “pass” or “qualified”. Level of ctDNA was defined as the maximum allele fraction (AF) for all known somatic alterations detected. Results: As of June 18, 2020, ctDNA analysis results were available for 470 of 540 patients with advanced solid tumors. Among them, we analyzed 70 advanced GU cancers (35 PC, 17 UC, and 18 RCC) and 400 non-GU cancers. The success rate of ctDNA was significantly lower in GU cancers than in non-GU cancers (81.4% vs. 91.5%, P = 0.016). The levels of ctDNA in PC and UC were similar to those in non-GU cancers. RCC had the second lowest ctDNA level (median 0.13%) after that in malignant melanoma. The median TMB, as estimated by ctDNA, was 4.40, 0.88 and 0.44 mutations/Mb in UC, PC and RCC, respectively. The most frequently altered genes were TP53 (34%), AR (11%), BRCA2 (11%), ATM (8.6%), and CDK12 (8.6%) in PC, TP53 (59%), TERT (41%), and CHEK2 (18%) in UC, and TP53 (22%), ATM (11%), and MTOR (11%) in RCC. The mutation rate in genes related to DNA damage response (DDR) pathways was significantly higher in GU cancers compared to that in non-GU cancers (30.0% vs. 18.0%, P = 0.033). However, other pathways were less frequently altered in GU cancers versus non-GU cancers, including Wnt (5.7% vs. 16.8%, P = 0.017), PI3K (8.6% vs. 19.0%, P = 0.039) and RAS/MAPK (8.6% vs. 29.5%, P < 0.001). Conclusions: Our results reveal the genomic landscape of ctDNA in several advanced solid tumors, and highlight the differences between tumor types. Comprehensive analysis of ctDNA using the F1L assay reveled alterations in DDR-associated genes were significantly more frequent in GU cancers than in non-GU cancers. Clinical trial information: UMIN000036749.

106 Background: Analysis of ctDNA has been utilized in pts with advanced GI cancer for identification of genomic alterations for targeted therapy. However, the characteristics of ctDNA genomic alterations of GI cancers compared to non-GI cancers remains unclear. Methods: Pts with advanced solid tumors were eligible in MONSTAR-SCREEN, a nationwide ctDNA screening project in Japan. Plasma samples were analyzed by an NGS-based 70-gene ctDNA assay, FoundationOne Liquid (F1L) at a CLIA-certified and CAP-accredited laboratory since Jul 2019. For treatment-naïve pts, tumor tissue samples were analyzed by FoundationOne CDx (F1CDx), a 324-gene tissue-based panel. Results: As of Jun 18 2020, out of enrolled 540 pts with advanced solid tumor, 470 pts, consisting of 133 with advanced GI cancers (67 colorectal, 48 gastric, 14 esophageal, 2 gastrointestinal tumor (GIST) and 2 small intestinal) and 337 non-GI cancers (103 hepatobiliary and pancreatic, 70 genitourinary, 64 breast, 46 head and neck, 33 gynecologic, and 21 skin), had an available ctDNA result. Sequencing success rate was similar between GI and non-GI cancers (91.7% vs. 89.3%, P = 0.50). GI cancers had a significantly higher ctDNA level (maximum variant allele fraction) than non-GI cancers (median, 11.8% vs. 0.57%; P = 1.6E-7). The most frequently altered genes were TP53 (73%), APC (73%), KRAS (30%), BRAF (15%), and PIK3CA (12%) in colorectal cancer, TP53 (44%), KRAS (19%), PIK3CA (15%), ATM (10%), and ERBB2 (10%) in gastric cancer, and TP53 (79%), ATM (21%), ERBB2 (21%) in esophageal cancer. Mutations in genes in pathways related to RAS/RAF/MEK (39.1 % vs. 21.4 %, P = 1.8E-4), receptor tyrosine kinase (20.3% vs 11.9%, P = 0.027), p53 (66.2% vs 49.6%, P = 0.0014), and Wnt (41.4% vs 4.7%, P = 4.4E-21) were significantly enriched in GI cancers compared to non-GI cancers. Tumor tissue samples were analyzed using F1CDx for 63 treatment-naïve pts, in which 51 (31.3%) of 132 alterations identified by F1L were not detected by F1CDx. Conclusions: GI cancers had higher ctDNA levels and distinct characteristics of ctDNA genomic alterations from non-GI cancers with an enrichment in several oncogenic pathways. One-third of ctDNA alterations were detected in only ctDNA, indicating the potential of ctDNA analysis to identify heterogenous genomic alterations in advanced GI cancer. Clinical trial information: UMIN000036749.

Outpatient pharmacy services were established since June 2009 for educating about the signs and symptoms that required treatment, explaining how to receive an emergency service, improving a patient's adherence, and managing side effects. In this study, we evaluated the usefulness of one of our outpatient pharmacy services, which aims to help patients receiving adjuvant chemotherapy including S-1 monotherapy for gastric cancer. In total, 34 and 80 patients received S-1 monotherapy without or with the intervention of outpatient pharmacy services, respectively; additionally, the median ages of the former and latter were 68 and 65 years, respectively. The treatment completion rates(82.4% versus 67.5%)were similar between the 2 groups(odds ratio[OR]: 0.45, 95% confidence interval[CI]: 0.16-1.21, p=0.106). Their emergency visit rates were 23.5% and 8.8%(OR: 0.31, 95% Cl: 0.10-0.94, p0.05). Emergency hospitalization was required for 8.8% and 0% of the population from each group(OR: 0.00, 95% CI: not significant, p0.05). We suggest that outpatient pharmacy services are useful because they are likely to improve a patient's safety.

Steroid is a key drug in cancer chemotherapy-induced emesis. However, it may sometimes cause inadequately controlled hyperglycemia. Ipragliflozin is a novel selective sodium-dependent glucose cotransporter 2 inhibitor of urinary glucose excretion. In this case, we controlled steroid-induced hyperglycemia by administering ipragliflozin. The case was a 47-year-old man who was diagnosed with Stage IV esophageal cancer (T3N2M1). He had type 2 diabetes. He was treated with cisplatin (70 mg/m2; day 1) and 5-FU (700 mg/m2; days 1-4) as radiochemotherapy. Intravenous infusion of dexamethasone (9.9 mg) was administered on day 1, followed by additional doses (6.6 mg) for 3 days, as one of the emetic therapies. He received intensive insulin therapy during the first course of chemotherapy, but had Grade 3 hyperglycemia regardless. For the next treatment course, we additionally administered ipragliflozin along with dexamethasone. As a result, the hyperglycemia subsided to Grade 2. These findings suggest that ipragliflozin suppresses steroid-induced hyperglycemia.