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The occurrence of immune-related adverse events (irAEs) after immune checkpoint inhibitors (ICIs) is unpredictable. Profiles of peripheral blood mononuclear cells (PBMCs) represent the host immune system and have the potential to predict irAEs. We analyzed PBMC subsets using multicolor flow cytometry before and at weeks 2 and 8 after the start of ICIs in patients with non-small cell lung cancer. Sixteen eligible patients were evaluated. The irAEs occurred in 6 patients (37.5%): diarrhea in 2, diarrhea and a rash in 1, pituitary dysfunction in 1, cholangitis in 1, and pneumonitis in 1. Patients experiencing irAEs had higher levels of CD86(+)plasmacytoid dendritic cells (pDCs) at the baseline and weeks 2 and 8 after the ICIs than those not experiencing irAEs (p = 0.005, 0.038, and 0.050, respectively). In patients experiencing irAEs, the levels of CD86(+)pDCs significantly decreased at weeks 2 and 8 compared to the baseline (p = 0 .034 and 0.025, respectively) but did not change in those not experiencing irAEs. The levels of other PBMC subsets were not significantly associated with irAEs. Higher levels of natural killer (NK) cells were significantly associated with an overall objective response (p = 0.024). In conclusion, higher levels of CD86(+)pDCs at the baseline and a reduction in those levels 2 and 8 weeks after ICIs were associated with the occurrence of irAEs. Higher levels of NK cells were associated with an objective response to ICIs. Evaluation of PBMCs may help to predict the efficacy and safety of ICIs.

It remains unclear whether the immunologic status of cells in peripheral blood can be used as a prognostic indicator of response to treatment for patients with unresectable metastatic colorectal cancer (MCRC). We therefore investigated the relationship between the pretreatment immunologic status of 40 patients with MCRC who planned to receive the first-line chemotherapy and their progression-free survival. Twenty-five immune cell subsets, including monocytic myeloid-derived suppressor cells (M-MDSC) and effector memory T cells (TEM), were measured by multicolor-flow cytometry. We divided patients into high and low (above and below the median, respectively) groups based on the median value for each immune cell subset and compared progression-free survival of the two groups. Patients with high M-MDSC, low CD4+ TEM, or low CD8+ TEM quantities had significantly shorter progression-free survival (P = 0.004, 0.005, and 0.002, respectively). Patients were classified into two prognostic groups based on numbers of adverse factors; having two or three adverse factors (n = 21, 52.5%) was correlated with significantly shorter progression-free survival compared with none or one (n = 19, 47.5%; P < 0.001). The presence of two or three adverse factors was an independent poor prognostic factor for progression-free survival (HR, 9.2; 95% confidence interval, 2.5–34.2; P < 0.001). These results provide evidence that pretreatment peripheral immune status can inform the outcome of patients with MCRC treated with first-line chemotherapy. Cancer Immunol Res; 4(7); 592–9. ©2016 AACR.

Supplemental Table 1 Combined assessment of quantities of two values from among M-MDSC, CD4+ TEM, and CD8+ TEM cells for correlation with PFS Supplemental Table 2 Comparison of patient characteristics between Group 1/2 and Group 3/4 Supplemental Table 3 Univariate analysis of the covariates patient characteristics and cytokines for PFS Supplemental Table 4 Comparisons of 10 cytokine concentrations in plasma between Group 1/2 and Group 3/4 Supplemental Figure 1 (A) Gating strategy and representative dot plots for G-MDSCs, DC (B) Gating strategy and representative dot plots for Treg, NK, Granzyme B+, Perforin+ and Ki-67+ cells Supplemental Figure 2 (A) Change in each immune cell type over time (B) Kaplan-Meier curves for PFS of patients who showed an increase or decrease in immune cells

Table S1. Pharmacokinetic parameters of encorafenib and alpelisib in patients at steady state (cycle 2 day 1). Table S2. Criteria for defining dose-limited toxicities. Supplementary Figure 1. Radiological images of response for a patient treated with the dual-combination therapy of encorafenib and cetuximab. Supplementary Figure 2. Time on study by response for patients treated with the dual-combination therapy of encorafenib and cetuximab and patients treated with the triple-combination therapy of encorafenib, alpelisib, and cetuximab.

Purpose: E7080, an oral multitargeted receptor tyrosine kinase inhibitor, has antiangiogenic and antitumor activity. This Phase I study investigated maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in patients with advanced solid tumors.Experimental Design: In this sequential, dose-escalation, open-label study E7080 was administered orally twice daily in a 2-week-on/1-week-off cycle. Plasma angiogenic proteins, circulating endothelial cells (CEC) and circulating progenitor cells (CEP) were measured for biomarker analysis.Results: Twenty-seven patients (median age 53 years, performance status 0/1) were enrolled. E7080 was escalated from 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg bid by conventional 3-patient cohorts. During cycle 1, no grade 3/4 toxicity was observed up to 13 mg bid. DLTs included grade 3 AST/ALT increase in 1 patient at 16 mg bid and grade 3 platelet count decrease in 2 patients at 20 mg bid. The MTD of 13 mg bid was determined. After repeated doses, Cmax and area under the plasma concentration–time curve increased in a dose-dependent manner. After 14 days' treatment, c-kit(+) CEPs and CECs significantly decreased in cycle 1, but c-kit(−) CEPs and CECs did not. Change from baseline in c-kit(+) CEC ratio in cycle 1 and baseline SDF1α, c-kit(+) CEPs and c-kit(+) CEP ratio significantly correlated with the E7080 therapeutic effect.Conclusion: E7080 has manageable toxicity up to 13 mg bid when administered in a 2-week-on/1-week-off cycle and shows preliminary activity for durable disease control. Biomarker analysis suggested antiangiogenic activity correlated with antitumor activity in patients with a wide range of solid tumors. Clin Cancer Res; 17(8); 2528–37. ©2011 AACR.

Supplementary Figure 1: Recurrence prediction comparison between CMS and MRC in the A) TCGA discovery and B) Validation cohorts.

Supplementary Table 2: Data of miRNAs which are analyzed in the TCGA discovery cohort with associated statistical parameters.

(A) Average body weight of mice treated with each BRAF inhibitor in the experiment depicted in Figure 1C; (B) Encorafenib plasma exposure in mice following the last dose from the experiment depicted in Figure 1C. To estimate daily exposure on the BID regimen, multiply the AUC x 2. Encorafenib is 98.6% protein bound in mouse plasma; (C) Gastric hyperplasia and hyperkeratosis observed in the forestomach of mice treated with BRAFi. Hematoxylin and eosin stains of forestomach sections from mice following 14 days of treatment with vehicle, encorafenib, dabrafenib, or vemurafenib from the study depicted in Figure 1C.

Supplementary Figure 4: MRC significantly predicted benefit of adjuvant chemotherapy in microsatellite stable stage III colorectal cancers KM plots depicted in panel A, B, C and D belong to MRC high risk category, while the KM plots in panel E, F, G and H belong to MRC low risk category. KM plots in panel A and E represents the analysis performed on combined stage II and III CRC patients, while panel B and F represents stage II analysis and panel C and G represents stage III patient's analysis separately. KM plots depicted in panel D and H represents the analysis performed on microsatellite stable stage III CRC patients.

Purpose: Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis. We evaluated encorafenib in a phase I study in patients with BRAFi treatment-naïve and pretreated BRAF-mutant melanoma.Experimental Design: The pharmacologic activity of encorafenib was first characterized preclinically. Encorafenib monotherapy was then tested across a range of once-daily (50–700 mg) or twice-daily (75–150 mg) regimens in a phase I, open-label, dose-escalation and -expansion study in adult patients with histologically confirmed advanced/metastatic BRAF-mutant melanoma. Study objectives were to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), characterize the safety and tolerability and pharmacokinetic profile, and assess the preliminary antitumor activity of encorafenib.Results: Preclinical data demonstrated that encorafenib inhibited BRAF V600E kinase activity with a prolonged off-rate and suppressed proliferation and tumor growth of BRAF V600E–mutant melanoma models. In the dose-escalation phase, 54 patients (29 BRAFi-pretreated and 25 BRAFi-naïve) were enrolled. Seven patients in the dose-determining set experienced dose-limiting toxicities. Encorafenib at a dose of 300 mg once daily was declared the RP2D. In the expansion phase, the most common all-cause adverse events were nausea (66%), myalgia (63%), and palmar–plantar erythrodysesthesia (54%). In BRAFi-naïve patients, the overall response rate (ORR) and median progression-free survival (mPFS) were 60% and 12.4 months [95% confidence interval (CI), 7.4–not reached (NR)]. In BRAFi-pretreated patients, the ORR and mPFS were 22% and 1.9 months (95% CI, 0.9–3.7).Conclusions: Once-daily dosing of single-agent encorafenib had a distinct tolerability profile and showed varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic melanoma. Clin Cancer Res; 23(18); 5339–48. ©2017 AACR.

Biochemical and cellular potency of encorafenib, dabrafenib, and vemurafenib in biochemical and cell-based assays. Purified BRAF V600E kinase domain was used in the biochemical experiments, using kinase-dead MEK1 as a substrate and a phosphorylated MEK1 (Ser217/221) alpha-screen readout. A375 cells were incubated with inhibitors for 3 hours to determine the phosphorylated ERK (pERK) half maximal effective concentration (EC50) and 72 hours to determine the proliferation EC50

Supplementary Figure 2: CONSORT diagram for patients and specimens from both fresh-frozen and FFPE clinical validation cohorts. A) Fresh-frozen cohort (cohort-1), B) FFPE cohort (cohorts 2 and 3).

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Supplementary Table 3: Spearman's rho correlation coefficients of MRC vs clinicopathological risk factors for all the clinical cohorts.

Purpose: The current tumor–node–metastasis (TNM) staging system is inadequate at identifying patients with high-risk colorectal cancer. Using a systematic and comprehensive biomarker discovery and validation approach, we aimed to identify an miRNA recurrence classifier (MRC) that can improve upon the current TNM staging as well as is superior to currently offered molecular assays.Experimental Design: Three independent genome-wide miRNA expression profiling datasets were used for biomarker discovery (N = 158) and in silico validation (N = 109 and N = 40) to identify an miRNA signature for predicting tumor recurrence in patients with colorectal cancer. Subsequently, this signature was analytically trained and validated in retrospectively collected independent patient cohorts of fresh-frozen (N = 127, cohort 1) and formalin-fixed paraffin-embedded (FFPE; N = 165, cohort 2 and N = 139, cohort 3) specimens.Results: We identified an 8-miRNA signature that significantly predicted recurrence-free interval (RFI) in the discovery (P = 0.002) and two independent publicly available datasets (P = 0.00006 and P = 0.002). The RT-PCR–based validation in independent clinical cohorts revealed that MRC-derived high-risk patients succumb to significantly poor RFI in patients with stage II and III colorectal cancer [cohort 1: hazard ratio (HR), 3.44 (1.56–7.45), P = 0.001; cohort 2: HR, 6.15 (3.33–11.35), P = 0.001; and cohort 3: HR, 4.23 (2.26–7.92), P = 0.0003]. In multivariate analyses, MRC emerged as an independent predictor of tumor recurrence and achieved superior predictive accuracy over the currently available molecular assays. The RT-PCR–based MRC risk score = (−0.1218 × miR-744) + (−3.7142 × miR-429) + (−2.2051 × miR-362) + (3.0564 × miR-200b) + (2.4997 × miR-191) + (−0.0065 × miR-30c2) + (2.2224 × miR-30b) + (−1.1162 × miR-33a).Conclusions: This novel MRC is superior to currently used clinicopathologic features, as well as National Comprehensive Cancer Network (NCCN) criteria, and works regardless of adjuvant chemotherapy status in identifying patients with high-risk stage II and III colorectal cancer. This can be readily deployed in clinical practice with FFPE specimens for decision-making pending further model testing and validation. Clin Cancer Res; 24(16); 3867–77. ©2018 AACR.See related commentary by Rodriguez et al., p. 3787

Supplementary Figure Legend from FOXQ1 Is Overexpressed in Colorectal Cancer and Enhances Tumorigenicity and Tumor Growth

Supplementary Figure Legends 1-2 from mTOR Signal and Hypoxia-Inducible Factor-1α Regulate CD133 Expression in Cancer Cells

Supplementary Figures 1-2 from mTOR Signal and Hypoxia-Inducible Factor-1α Regulate CD133 Expression in Cancer Cells

Supplementary Figure 1 from FOXQ1 Is Overexpressed in Colorectal Cancer and Enhances Tumorigenicity and Tumor Growth

Supplementary Tables 1-2 from FOXQ1 Is Overexpressed in Colorectal Cancer and Enhances Tumorigenicity and Tumor Growth

Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family, and it has recently been proposed to participate in gastric acid secretion and mucin gene expression in mice. However, the role of FOXQ1 in humans and especially in cancer cells remains unknown. We found that FOXQ1 mRNA is overexpressed in clinical specimens of colorectal cancer (CRC; 28-fold/colonic mucosa). A microarray analysis revealed that the knockdown of FOXQ1 using small interfering RNA resulted in a decrease in p21CIP1/WAF1 expression, and a reporter assay and a chromatin immunoprecipitation assay showed that p21 was one of the target genes of FOXQ1. Stable FOXQ1-overexpressing cells (H1299/FOXQ1) exhibited elevated levels of p21 expression and inhibition of apoptosis induced by doxorubicin or camptothecin. Although cellular proliferation was decreased in H1299/FOXQ1 cells in vitro, H1299/FOXQ1 cells significantly increased tumorigenicity [enhanced green fluorescent protein (EGFP): 2/15, FOXQ1: 7/15] and enhanced tumor growth (437 ± 301 versus 1735 ± 769 mm3, P < 0.001) in vivo. Meanwhile, stable p21 knockdown of H1299/FOXQ1 cells increased tumor growth, suggesting that FOXQ1 promotes tumor growth independent of p21. Microarray analysis of H1299/EGFP and H1299/FOXQ1 revealed that FOXQ1 overexpression upregulated several genes that have positive roles for tumor growth, including VEGFA, WNT3A, RSPO2, and BCL11A. CD31 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining of the tumor specimens showed that FOXQ1 overexpression mediated the angiogenic and antiapoptotic effect in vivo. In conclusion, FOXQ1 is overexpressed in CRC and enhances tumorigenicity and tumor growth presumably through its angiogenic and antiapoptotic effects. Our findings show that FOXQ1 is a new member of the cancer-related FOX family. Cancer Res; 70(5); 2053–63

The underlying mechanism regulating the expression of the cancer stem cell/tumor-initiating cell marker CD133/prominin-1 in cancer cells remains largely unclear, although knowledge of this mechanism would likely provide important biological information regarding cancer stem cells. Here, we found that the inhibition of mTOR signaling up-regulated CD133 expression at both the mRNA and protein levels in a CD133-overexpressing cancer cell line. This effect was canceled by a rapamycin-competitor, tacrolimus, and was not modified by conventional cytotoxic drugs. We hypothesized that hypoxia-inducible factor-1α (HIF-1α), a downstream molecule in the mTOR signaling pathway, might regulate CD133 expression; we therefore investigated the relation between CD133 and HIF-1α. Hypoxic conditions up-regulated HIF-1α expression and inversely down-regulated CD133 expression at both the mRNA and protein levels. Similarly, the HIF-1α activator deferoxamine mesylate dose-dependently down-regulated CD133 expression, consistent with the effects of hypoxic conditions. Finally, the correlations between CD133 and the expressions of HIF-1α and HIF-1β were examined using clinical gastric cancer samples. A strong inverse correlation (r = −0.68) was observed between CD133 and HIF-1α, but not between CD133 and HIF-1β. In conclusion, these results indicate that HIF-1α down-regulates CD133 expression and suggest that mTOR signaling is involved in the expression of CD133 in cancer cells. Our findings provide a novel insight into the regulatory mechanisms of CD133 expression via mTOR signaling and HIF-1α in cancer cells and might lead to insights into the involvement of the mTOR signal and oxygen-sensitive intracellular pathways in the maintenance of stemness in cancer stem cells. [Cancer Res 2009;69(18):7160–4]

Background Although cisplatin and 5-chloro-2,4-dihydropyrimidine (dihydropyrimidine dehydrogenase inhibitor contained in S-1) are excreted into the urine, it remains unknown how creatinine clearance (CrCl) affects the safety and efficacy of cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 in patients with advanced gastric cancer. Methods Among the 741 participants in JCOG1013 comparing cisplatin plus S-1 with docetaxel plus cisplatin plus S-1, 723 with serum creatinine levels ≤1.2 mg/dL were categorized into A1 (CrCl ≥ 80 mL/min), A2 (60 ≤ CrCl Results The numbers of patients categorized as A1/A2/A3 and B1/B2/B3 were 169/136/57 and 170/138/53, respectively. In the cisplatin plus S-1 arm, a lower CrCl was associated with higher incidences of grade 4 leukopenia (P = 0.006), neutropenia (P = 0.002), and grade 3/4 anorexia (P = 0.004) and febrile neutropenia (P = 0.049), whereas there was no association in the docetaxel plus cisplatin plus S-1 arm. No significant differences were observed according to CrCl in the overall survival [median: 15.4/15.5/15.4 months in A1/A2/A3 (P = 0.886) and 15.3/13.7/13.7 months in B1/B2/B3 (P = 0.719)], progression-free survival [median: 7.1/6.8/6.2 months in A1/A2/A3 (P = 0.884) and 7.5/7.2/7.8 months in B1/B2/B3 (P = 0.851)] and response rates [58.9/57.8/46.9% in A1/A2/A3 (P = 0.311) and 62.0/61.5/51.5% in B1/B2/B3 (P = 0.362)]. Conclusions Renal impairment was associated with severe adverse events in cisplatin plus S-1 therapy but not with the efficacy in cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 therapy.

Background: The immune-related adverse events (irAEs) is unpredictable. Peripheral blood mononuclear cell (PBMC) profiles have potential for predicting irAEs. Methods: PBMCs were measured using multicolor flow cytometry before and at weeks 2 and 8 after the immune checkpoint inhibitors (ICIs) in lung cancere patients. Results: Sixteen patients were eligible for the analysis. The irAEs occurred in 6 (37.5%) patients. Patients with irAEs demonstrated higher levels of CD86+plasmacytoid dendritic cells (pDCs) at baseline and weeks 2 and 8 after the ICIs than patients without irAEs (p = 0.005, 0.038, and 0.050, respectively). Higher levels of natural killer (NK) cells were significantly associated with overall objective response (p = 0.024). Conclusions: Higher levels of CD86+pDCs at baseline and the reduction at 2 and 8 weeks after the ICIs were associated with the occurrence of irAEs. Higher levels of NK cells were associated with therapeutic efficacy. Measurements of PBMCs may be useful for predicting the efficacy and safety of ICIs.

Background: The occurrence of immune-related adverse events (irAEs) after immune checkpoint inhibitors (ICIs) is unpredictable. Peripheral blood mononuclear cell (PBMC) profiles, representing host immune status, have potential for predicting irAEs. Methods: PBMC subsets were measured using multicolor flow cytometry before and at weeks 2 and 8 after the initiation of ICIs in patients with non-small cell lung cancer. Results: Sixteen evaluable patients were eligible for the analysis. The following irAEs occurred in 6 (37.5%) patients: diarrhea (n = 2), diarrhea and rash (n = 1), pneumonitis (n = 1), pituitary dysfunction (n = 1), and cholangitis (n = 1). Patients with irAEs demonstrated higher levels of CD86+plasmacytoid dendritic cells (pDCs) at baseline and weeks 2 and 8 after the ICIs than patients without irAEs (p = 0.005, 0.038, and 0.050, respectively). In patients with irAEs, the levels of CD86+pDCs decreased at weeks 2 and 8 compared with baseline (p =0 .034 and 0.025, respectively) but did not change in patients without irAEs. Other PBMC subsets had no significant associations with irAEs. Higher levels of natural killer (NK) cells were significantly associated with overall objective response (p = 0.024). Conclusions: Higher levels of CD86+pDCs at baseline and the reduction at 2 and 8 weeks after the ICIs were associated with the occurrence of irAEs. Higher levels of NK cells were associated with therapeutic efficacy. Measurements of PBMCs may be useful for predicting the efficacy and safety of ICIs.

Although fluoropyrimidine plus oxaliplatin is the standard of care for stage III colon cancer, fluoropyrimidine alone is also recommended for stage III patients in Japanese and other practice guidelines. We assessed efficacy of adjuvant fluoropyrimidine with or without oxaliplatin across a population of patients with stage III colon cancer in the Multi-Institutional Registry of Large Bowel Cancer in Japan. From the registry, we analyzed 6,834 stage III colorectal cancer patients. Approximately 70% of colorectal cancer patients received some form of chemotherapy. Of these, we analyzed those who received adjuvant chemotherapy between 2008 and 2011. Based on the TNM classification, the 5-year overall survival rates of colon and rectal cancer after the covariate adjustment by regimens of adjuvant chemotherapy were 95.7% with fluoropyrimidines and 90.6% with oxaliplatin-combined therapy at stage IIIA (Stratified log-rank P < 0.001), 86.5% and 80.8% at stage IIIB (P < 0.001), and 72.1% and 70.7% at stage IIIC (P < 0.001), respectively. Oxaliplatin did not enhance efficacy with regard to relapse-free survival as well as overall survival. Adjuvant fluoropyrimidine monotherapy and fluoropyrimidine plus oxaliplatin show comparable efficacy benefits for the treatment of stage III of Japanese colon cancer patients. This supports the use of fluoropyrimidine alone as a standard option for this patient group in Japan.

Identifying patients resistant to cisplatin treatment is expected to improve cisplatin-based chemotherapy for various types of cancers. Excision repair cross-complementing group 1 (ERCC1) is involved in several repair processes of cisplatin-induced DNA crosslinks. ERCC1 overexpression is reported as a candidate prognostic factor and considered to cause cisplatin resistance in major solid cancers. However, anti-ERCC1 antibodies capable of evaluating expression levels of ERCC1 in clinical specimens were not fully optimized. A mouse monoclonal antibody against human ERCC1 was generated in this study. The developed antibody 9D11 specifically detected isoforms of 201, 202, 203 but not 204, which lacks the exon 3 coding region. To evaluate the diagnostic usefulness of this antibody, we have focused on gastric cancer because it is one of the major cancers in Japan. When ERCC1 expression was analyzed in seventeen kinds of human gastric cancer cell lines, all the cell lines were found to express either 201, 202, and/or 203 as major isoforms of ERCC1, but not 204 by Western blotting analysis. Immunohistochemical staining showed that ERCC1 protein was exclusively detected in nuclei of the cells and a moderate level of constant positivity was observed in nuclei of vascular endothelial cells. It showed a clear staining pattern in clinical specimens of gastric cancers. Antibody 9D11 may thus be useful for estimating expression levels of ERCC1 in clinical specimens.

Capecitabine plus oxaliplatin, CAPOX, therapy is one of the standardized options for adjuvant chemotherapy for colorectal cancer, but the efficacy and the safety of CAPOX in elderly patients are unclear. In this study, we investigated the relative dose intensity (RDI) and reasons for dose reduction in patients over the age of 70 (elderly group) (n = 12) and those under the age of 70 (non-elderly group) (n = 24) receiving adjuvant CAPOX therapy for colorectal cancer. The median RDIs were 71.1% in the elderly group and 67.9% in the non-elderly group for oxaliplatin (p = 0.416), and 81.6% and 86.4% for capecitabine (p = 0.166), respectively. The rate of peripheral neuropathy which was the reason for dose reduction of oxaliplatin was approximately 4.5-fold higher in the non-elderly group than in the elderly group. In addition, hematologic toxicity was the most common reason for dose reduction at 50.0% in the elderly group. The results of this study suggested that a similar therapeutic intensity can be maintained in elderly patients relative to non-elderly patients by appropriate dose reduction and discontinuation of drug treatments. Elderly patients are more susceptible to hematologic toxicity than to peripheral neuropathy.

This study aimed to evaluate the influence of CYP2D6 activity and cachexia progression on the enantiomeric alteration of plasma tramadol and its demethylated metabolites in head and neck cancer patients. Fifty-three head and neck cancer patients receiving oral tramadol were enrolled. The plasma concentrations of tramadol, O-desmethyltramadol (ODT), and N-desmethyltramadol (NDT) enantiomers were determined. The CYP2D6 activity score (AS) and degree of cachexia progression were assessed according to genotype and the Glasgow Prognostic Score (GPS), respectively. The enantiomeric ratio of NDT was (+)-form dominant in all patients. CYP2D6 AS had negative correlations with the plasma concentrations of (+)-NDT and (−)-NDT. The plasma concentrations of (+)-tramadol and (+)-ODT were higher in patients with GPS 1 or 2 than in those with GPS 0. Lower metabolic ratios to NDT enantiomers were observed in patients with GPS 1 or 2. In patients with GPS 1 or 2, the plasma (−)-tramadol was associated with the incidence of central nervous system symptoms. In conclusion, CYP2D6 AS partially explained the contribution of CYP2D6 activity to plasma tramadol and its demethylated metabolite enantiomers. Additionally, cachexia progression elevated the plasma (+)-tramadol and (+)-ODT levels through the reduction of N-demethylation of (+)-tramadol.

Mechanisms accounting for sex differences in the incidence of adverse events caused by fluoropyrimidine treatments, and histologic differences in efficacy are insufficiently understood. We determined differences between the sexes in terms of the safety of S-1 plus oxaliplatin (SOX)/bevacizumab-versus-l-leucovorin, 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX)/bevacizumab, and the impact of histology on their therapeutic effects, in 512 unresectable metastatic colorectal cancer patients from the SOFT phase III study. Nausea (OR: 2.88, P < 0.001) and vomiting (OR: 3.04, P = 0.005) occurred more frequently in females than males treated with SOX/bevacizumab, while nausea (OR: 2.12, P = 0.006), vomiting (OR: 3.26, P = 0.004), leukopenia (OR: 2.61, P < 0.001), neutropenia (OR: 2.92, P < 0.001), and alopecia (OR: 4.13, P < 0.001) were higher in females on FOLFOX/bevacizumab. Mean relative dose intensities (RDIs) of S-1 during all cycles of SOX/bevacizumab were significantly lower in females (73.9%) than males (81.5%) (P < 0.001), while RDIs of continuous infusion of 5-FU in the FOLFOX/bevacizumab regimen were 75.0% in females and 80.5% in males (P = 0.005). No significant differences in efficacy with regard to overall survival (OS) and progression-free survival (PFS) were identified between the sexes for either SOX/bevacizumab or FOLFOX/bevacizumab treatment. Patients with poorly-differentiated adenocarcinoma had significantly worse OS (HR: 2.72, 95% CI: 1.67-4.44, P < 0.0001) and PFS (HR: 1.89, 95% CI: 1.18-3.02, P = 0.0079) than patients with well- or moderately-differentiated adenocarcinoma. Female patients experienced more frequent and severe adverse reactions to SOX/bevacizumab and FOLFOX/bevacizumab and a worse prognosis for poorly-differentiated adenocarcinoma were confirmed in this phase III study. This warrants further translational research to identify the responsible mechanisms.

Metabolic reprogramming, including the Warburg effect, is a hallmark of cancer. Indeed, the diversity of cancer metabolism leads to cancer heterogeneity, but accurate assessment of metabolic properties in tumors has not yet been undertaken. Here, we performed absolute quantification of the expression levels of 113 proteins related to carbohydrate metabolism and antioxidant pathways, in stage III colorectal cancer surgical specimens from 70 patients. The Warburg effect appeared in absolute protein levels between tumor and normal mucosa specimens demonstrated. Notably, the levels of proteins associated with the tricarboxylic citric acid cycle were remarkably reduced in the malignant tumors which had relapsed after surgery and treatment with 5‐fluorouracil‐based adjuvant therapy. In addition, the efficacy of 5‐fluorouracil also decreased in the cultured cancer cell lines with promotion of the Warburg effect. We further identified nine and eight important proteins, which are closely related to the Warburg effect, for relapse risk and 5‐fluorouracil benefit, respectively, using a biomarker exploration procedure. These results provide us a clue for bridging between metabolic protein expression profiles and benefit from 5‐fluorouracil adjuvant chemotherapy., Using absolute quantification of protein levels, we identified that the behavior of Warburg effect‐related proteins was strongly associated with relapse prediction and the therapeutic indication of uracil‐tegafur (UFT)‐adjuvant therapy.

A liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) method is a novel approach for the quantification of therapeutic monoclonal antibody. However, this method has severe ionization suppression and time-consuming sample preparation. In the present study, we developed a simple and rapid LC-MS/MS method for quantifying serum nivolumab with good analytical performance using immunoglobulin G (IgG) purification and immobilized tryptic digestion. Surrogate peptide derived from nivolumab was identified by a hybrid quadrupole-Orbitrap mass spectrometer. IgG purification and immobilized tryptic digestion were completed within 25 minutes. The chromatographic separation was completed in 10 minutes with stepwise-gradient elution. Chromatographic peaks interfering with the surrogate peptide and its stable isotope-labeled peptide as an internal standard were not observed from serum digests. The dynamic range of the calibration curve was 2–200 μg mL−1. The intra- and inter-assay accuracies and imprecisions were 92.2–104.5% and less than 10.0%, respectively. Serum nivolumab concentrations ranged from 12–112 μg mL−1 in 14 cancer patients. The measured concentrations in the LC-MS/MS method were strongly correlated with those in the ELISA method (r = 0.92, P < 0.01). In conclusion, a simple and rapid LC-MS/MS method for quantifying serum nivolumab using immobilized tryptic digestion coupled to IgG purification was found to be acceptable for clinical settings.

Purpose: Several studies have shown that fluoropyrimidine plus oxaliplatin (SOX) is non-inferior to fluoropyrimidine plus cisplatin as first-line chemotherapy for advanced gastric cancer. We investigated retrospectively the choice of second-line regimen, along with the proportion and feasibility of paclitaxel-containing regimen, in the subsequent treatment of patients with advanced gastric cancer treated with SOX as first-line chemotherapy. Materials and Methods: We retrospectively analyzed the impact of oxaliplatin-induced neuropathy on both the choice of subsequent regimens and feasibility of subsequent chemotherapy with paclitaxel, focusing on patients with advanced gastric cancer who received S-1 plus oxaliplatin as first-line chemotherapy. Results: Twenty-seven from a total of 31 patients enrolled into the phase 2 and phase 3 study assessing S-1 plus oxaliplatin were analyzed (4 patients were deemed ineligible). Among 24 patients that had received second-line treatment, paclitaxel was not selected in 2 patients due to oxaliplatin-induced neuropathy. Paclitaxel was selected as second-line chemotherapy in 16 patients, as third-line chemotherapy in 6 patients and fourth-line chemotherapy in one patient. Severity of sensory neuropathy was grade 0/1/2/3 in 11/10/2/0 patients, respectively, immediately before treatment with paclitaxel, while the worst toxicity profile during paclitaxel treatment was grade 0/1/2/3 in 7/13/1/2 patients, respectively. Although there were no patients requiring dose reductions of paclitaxel due to neuropathy, 2 patients discontinued paclitaxel use due to grade 3 sensory neuropathy after 4 or 8 administrations of paclitaxel. Conclusion: Oxaliplatin-induced neuropathy during first-line chemotherapy may affect the choice and feasibility of subsequent chemotherapy with paclitaxel in advanced gastric cancer patients.

510 Background: Currently 6 regimens are available for advanced hepatocellular carcinoma (HCC) in Japan, including atezolizumab plus bevacizumab (AB), sorafenib (S), and lenvatinib (L) for first-line treatment and regorafenib (R), ramucirumab (RAM), and cabozantinib (C) for the second-line treatment. In real-world clinical practice, the number of combinations of treatment sequences is enormous. We have launched a nationwide registry of systemic therapy for HCC named Hepatoma Registry of Integrating and Aggregating Electric Health Records (HERITAGE). Methods: The HERITAGE is linked to the nationwide follow-up survey of the Japan Liver Cancer Association; cases treated with systemic therapy between 2015 and 2022 were included in the current study. Information on treatment efficacy and duration was collected and registered on each treatment regimen. Results: As of June 2022, 6,400 treatment lines (S 2,319, L 2559, AB 768, R 406, RAM 251, C 71) in 4,307 cases were enrolled. The response rates, disease control rates, and median treatment duration of each sequence of regimens are shown in the table. The 1st line regimen, S, L, and AB, were also used as the second and later lines in Japan and found as effective as if used as the 1st line treatment. Limitation: No adjustments for clinical conditions were performed. Conclusions: We have demonstrated the efficacy of various treatment sequences in a sufficient number of cases. Clinical trial information: UMIN000046567 . [Table: see text]

179 Background: TP53 tumor suppressor gene is frequently inactivated by loss-of-function mutations. Some of the mutations gain additional oncogenic functions and are known as gain-of-function (GOF) mutations. This study analyzed the association among primary tumor site (PS), genome-wide DNA methylation status (GWMS), and TP53 mutation subtypes about prognosis in metastatic colorectal cancer (mCRC). Methods: Tumor tissues of mCRC patients registered in the TRICOLORE Study (clinical trial number) were analyzed for GWMS and TP53 mutation as translational research and were classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC) for GWMS, and wild-type , GOF mutation and non-GOF mutation for TP53 mutation. Overall survival (OS) was compared between single or combined subgroups, and Cox regression analysis was performed to identify factors contributing to OS. Results: A total of 209 patients were analyzed, HMCC and LMCC were 60 (28.7%) and 149 (71.3%), respectively. TP53 wild-type , GOF mutation and non-GOF mutation were 35 (16.7%), 79 (37.8%) and 95 (45.5%), respectively. HMCC showed a significantly worse prognosis than LMCC (median OS 25.3 vs. 40.3 months, P < 0.01, hazard ratio 1.87). Combining GWMS and TP53 mutation subtypes about prognosis, the HMCC/GOF (n = 26) group had a significantly poorer prognosis than the other three groups including HMCC/non-GOF (n = 22), LMCC/GOF (n = 53), and LMCC/non-GOF groups (n = 73) (median OS 17.7, 35.3, 40.3, 41.2 months, p = 0.007, p < 0.001, p < 0.001, respectively). The HMCC/GOF group had a poorer prognosis than the other 3 groups regardless of the PS. In the multivariate analysis in the GOF mutation subgroup, HMCC (p < 0.01) was the only poor prognostic factor, while right-sided colon cancer (p = 0.03) and RAS mutations (p = 0.01) were significant poor prognostic factors in the multivariate analysis in the non-GOF mutation subgroup. Conclusions: TP53 gain of function mutations are independent poor prognostic factors in high-methylated metastatic colorectal cancer.

342 Background: We previously reported that performance status (PS) ≥1, no prior gastrectomy, number of metastatic sites ≥2, and high serum ALP level are poor prognosis factors and proposed a JCOG prognostic index by analyzing the data of advanced gastric cancer (AGC) patients enrolled in JCOG9912 (Takahari D et al. Oncologist 2014). Recently, Neutrocyte/ Lymphocyte Ratio (NLR) and diffuse type of cancer have also been reported to be prognostic factors of AGC. Methods: Prognostic factors were assessed in patients with AGC who enrolled in JCOG1013, the phase III study comparing docetaxel, cisplatin, and S-1 (DCS) versus cisplatin and S-1 (CS) in first-line treatment (Yamada Y et al. Lancet Gastroenterol Hepatol. 2019) was retrospectively evaluated using a Cox proportional regression model. The overall adequacy of risk prediction in the modified JCOG prognostic index and the original index were assessed by C-statistics. Results: Among 741 patients, 730 with all data for this analysis were selected. The median overall survival (OS) was 14.9 months (95% confidence interval [CI], 14.1–15.8). The median OS of the good (n=233), moderate (n=444), and poor (n=53) risk groups by the original JCOG index was 19.0, 14.2, and 9.1 months, respectively. The HRs compared with the good group were 1.59 [95% CI, 1.33–1.89; p < 0.0001] in the moderate group, and 2.47 [95% CI, 1.81–3.38; p < 0.0001] in the poor group with C-statistics of 0.572. In the multivariable analysis of 7 factors which showed p

The phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second‐line treatment for metastatic colorectal cancer. We evaluated the associations between the UGT1A1 genotype linked to adverse events—caused by irinotecan—and the efficacy and safety of mXELIRI and FOLFIRI. The UGT1A1 genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression‐free survival, response rate, and safety were assessed. The UGT1A1 genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12‐2.09; P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62‐1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79‐1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39‐1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second‐line chemotherapy in terms of efficacy and safety regardless of the UGT1A1 genotype., Capecitabine plus irinotecan (XELIRI) with or without bevacizumab is noninferior to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab in terms of overall survival, regardless of UGT1A1 genotype. Additionally, modified XELIRI with or without bevacizumab showed a favorable tolerability profile that was comparable to that of FOLFIRI with or without bevacizumab among all UGT1A1 genotypes.

Previous studies have shown sex‐related differences in the incidence of adverse events following treatment with fluoropyrimidines, however the mechanism of this difference is unknown. We examined sex‐related differences in the safety of S‐1 plus oxaliplatin (SOX) and S‐1 plus cisplatin (CS) in 663 metastatic gastric cancer patients taking part in a phase III study. The incidences of leukopenia (odds ratio [OR] 1.9; P = .015), neutropenia (OR 2.2; P = .002), nausea (OR 2.0; P = .009), and vomiting (OR 2.8; P

Definitive chemoradiotherapy is one of the treatment options for locally advanced esophageal cancer with curative intent. Esophagitis and pharyngitis are well-known adverse events that occur during chemoradiotherapy, but gastric mucosal injury has been less frequently reported compared to mucositis. Importantly, gastric mucosal injury is not well known, hard to manage, and sometimes fatal. Hence, we examined the clinical characteristics and the incidence of gastric mucosal injury after CRT for esophageal cancer. The medical records of patients who received definitive chemoradiotherapy combined with 5-fluorouracil and cisplatin for stage II/III (nonT4) esophageal squamous cell carcinoma from January 2001 to December 2010 at our institute were reviewed retrospectively. We investigated 256 patients in whom, data for endoscopic abdomen examinations were both before and after CRT were available. Gastric mucosal damage was observed in 90 patients (35%) (grade 1/2/3 = 69/18/3). One of the possible risk factors identified in this study was the irradiation dose to abdomen. Compared to patients with cervical esophagus–upper thoracic esophagus tumor location, patients with middle thoracic esophagus–abdominal esophagus tumor location were more likely to develop gastric mucosal damage, although there was no statistically significant difference. It is important to consider gastric mucosal injury in patients who receive CRT, particularly when the irradiation field includes stomach.