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STUDY OBJECTIVES: Biological models suggest that obstructive sleep apnea (OSA) is potentially carcinogenic. We aimed to clarify the inconsistent epidemiological literature by considering various traditional and novel OSA severity indices. METHODS: We systematically searched PubMed, Embase, Scopus, and the Cochrane Library for observational or randomized studies of associations of OSA, measured by diagnostic codes or any index, each with all-cancer incidence or mortality in adults, compared with participants with no/mild OSA. Two reviewers independently selected studies, extracted data, and evaluated study bias using the Newcastle-Ottawa scale and quality of evidence using GRADE (Grading of Recommendations Assessment, Development, and Evaluation). We performed inverse variance-weighted, random-effects meta-analyses and sensitivity analyses. RESULTS: We included 20 observational studies (5,340,965 participants), all with moderate/low bias, from 1,698 records. Based on T90 (sleep duration with oxygen saturation < 90%), patients with OSA who had moderate (T90 > 1.2%, hazard ratio [HR] = 1.28, 95% confidence interval [CI] = 1.07–1.54) and severe nocturnal hypoxemia (T90 > 12%, HR = 1.43, 95% CI = 1.16–1.76) experienced 30%–40% higher pooled all-cancer risk than normoxemic patients, after multiple adjustment for covariates including obesity. Furthermore, severe nocturnal hypoxemia nearly tripled all-cancer mortality (HR = 2.66, 95% CI = 1.21–5.85). Patients with apnea-hypopnea index–defined severe OSA, but not moderate OSA, had higher all-cancer risk (HR = 1.18, 95% CI = 1.03–1.35) but similar all-cancer mortality as patients without OSA. An OSA diagnosis was not associated with all-cancer risk. Evidence quality ranged from low to moderate. Insufficient evidence was available on the oxygen desaturation index, lowest/median saturation, and arousal index. CONCLUSIONS: In patients with OSA, nocturnal hypoxemia is independently associated with all-cancer risk and mortality. Future studies should explore if risk differs by cancer type, and whether cancer screening and OSA treatment are beneficial. SYSTEMATIC REVIEW REGISTRATION: Registry: PROSPERO; URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=220836; Identifier: CRD42021220836. CITATION: Tan BKJ, Teo YH, Tan NKW, et al. Association of obstructive sleep apnea and nocturnal hypoxemia with all-cancer incidence and mortality: a systematic review and meta-analysis. J Clin Sleep Med. 2022;18(5):1427–1440.

ObjectiveTo date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery.DesignThe primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort.ResultsFrom the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction pConclusionUsing machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit.Trial registration numberUMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial)

PURPOSE The US Food and Drug Administration has granted regulatory approval for the use of nivolumab—an immune checkpoint inhibitor (ICI)—in the first-line treatment of advanced gastric or esophageal adenocarcinoma (GEAC), regardless of programmed death-ligand 1 (PD-L1) expression. However, the efficacy of ICIs in low PD-L1–expressing tumors remains unclear. MATERIALS AND METHODS This study aims to reconstruct unreported Kaplan-Meier (KM) plots of PD-L1 combined positive score (CPS) subgroups of randomized phase III trials comparing the addition of ICIs with conventional chemotherapy in the first-line treatment of GEAC. A graphical reconstructive algorithm was adopted to estimate time-to-event outcomes from reported overall survival and progression-free survival (OS and PFS) KM plots describing overall or subgroup cohorts. Using reconstructed time-to-event outcomes, KMSubtraction conducts bipartite matching of patients from the reported subgroup among the overall cohort. By excluding matched patients, KM plots and survival analyses of the unreported subgroups were retrieved. RESULTS CheckMate-649, KEYNOTE-062, and KEYNOTE-590 were included. Two PD-L1 subgroups were identified with data unreported in the primary manuscripts: PD-L1 CPS 1-4 from CheckMate-649 and PD-L1 CPS 1-9 from KEYNOTE-062. No significant differences in OS and PFS were demonstrated in ICI-chemotherapy combinations when compared with chemotherapy among CheckMate-649 PD-L1 CPS 1-4 (OS: hazard ratio [HR] = 0.950, 95% CI, 0.747 to 1.209, P = .678; PFS: HR = 0.958, 95% CI, 0.743 to 1.236, P = .743) and KEYNOTE-062 PD-L1 CPS 1-9 subgroups. In the KEYNOTE-062 PD-L1 CPS 1-9 subgroup, patients treated with pembrolizumab had an increased hazard of tumor progression (HR = 2.092, 95% CI, 1.661 to 2.635, P < .001). CONCLUSION Using KMSubtraction, data of PD-L1 subgroups previously unreported by primary manuscripts of pivotal clinical trials were retrieved. These data suggest the lack of benefit in the addition of ICI to chemotherapy in low PD-L1–expressing GEAC tumors.

Small bowel adenocarcinoma (SBA) is a rare neoplasm that is associated with Crohn’s disease (CD). This study aims to quantify the prevalence of CD-SBA, review the current evidence of histopathology and molecular analysis findings, and identify the clinical presentation and outcomes of CD-SBA. Electronic databases Medline and Embase were searched for articles describing SBA in inflammatory bowel disease patients. The histopathology, molecular analysis findings, clinical presentation, prevalence, and outcomes of CD-SBA were extracted, and results were pooled with random effects. In total, 33 articles were included in the analysis. Prevalence of SBA was 1.15 (CI: 0.31–2.33) per 1000 CD patients. Only 11% (CI: 0.04–0.21) of CD-SBA patients had observable radiological features. CD-SBA was most commonly found in the ileum (84%), diagnosed at stage 2 (36%), with main presenting complaints including obstruction, weight loss, and abdominal pain. Significant histopathological findings included adjacent epithelial dysplasia, and an equal distribution of well-differentiated (49%) and poorly differentiated subtypes (46%). Most prevalent genetic mutation was KRAS mutation (18%), followed by mismatch repair deficiency (9.7%). The 5-year overall survival for CD-SBA patients was 29% (CI: 0.18–0.41), and 33% (CI: 0.26–0.41) for de novo SBA. No statistically significant increase in risk for CD-SBA was noted for treatment with thiopurines, steroids, and 5-ASA. Our meta-analysis found the prevalence of CD-SBA to be 1.15 per 1000 CD patients. The 5-year overall survival for CD-SBA was poor. The presenting symptoms were non-specific, and therefore the diagnosis requires a high index of suspicion.

Introduction Peritoneal carcinomatosis is difficult to treat. Pressurized Intra-Peritoneal Aerosolised Chemotherapy (PIPAC) is a novel method of delivering chemotherapy to the peritoneal cavity, aiming for homogenous and deeper drug distribution. To date, limited chemotherapeutics have been used with promising results. Here, we evaluate the pharmacokinetics, peritoneal tissue drug concentration, penetration, and short-term safety of PIPAC using solvent-based paclitaxel in swine to guide clinical trials. Materials and methods PIPAC solvent-based paclitaxel was administered at 60, 30, and 15mg/m2 for 3 cohorts. Each PIPAC procedure was followed by intravenous (IV) administration of the same dose of solvent-based paclitaxel on Day 7, serving as control for pharmacokinetic comparison in the same pig. Safety and toxicity were evaluated by clinical assessment, blood counts and biochemistry. Blood samples were taken for pharmacokinetic analysis. Peritoneal biopsies were taken to measure tissue paclitaxel concentrations and distribution. Results 12 Yorkshire x Landrace pigs underwent trial procedures. With PIPAC, there was linear pharmacokinetics and lower systemic exposure to paclitaxel compared to IV administration. MALDI-MSI demonstrated concentration of paclitaxel at the peritoneal surface, with estimated 2 mm penetration. PIPAC paclitaxel had favorable toxicity profile. The most significant adverse event was neutropenia which was dose dependent, with absolute neutrophil count Conclusion PIPAC paclitaxel at 15mg/m2 may be considered for a Phase I study.

Gastric cancer cases are often diagnosed at an advanced stage with poor prognosis. Platinum-based chemotherapy has been internationally accepted as first-line therapy for inoperable or metastatic gastric cancer. To achieve greater benefits, selection of patients eligible for this treatment is critical. Although gene expression profiling has been widely used as a genomic classifier to identify molecular subtypes of gastric cancer and to stratify patients for different chemotherapy regimens, its prediction accuracy can be improved. Adenosine-to-inosine (A-to-I) RNA editing has emerged as a new player contributing to gastric cancer development and progression, offering potential clinical utility for diagnosis and treatment. Using a systematic computational approach followed by both in vitro validations and in silico validations in The Cancer Genome Atlas (TCGA), we conducted a transcriptome-wide RNA editing analysis of a cohort of 104 patients with advanced gastric cancer and identified an RNA editing (GCRE) signature to guide gastric cancer chemotherapy. RNA editing events stood as a prognostic and predictive biomarker in advanced gastric cancer. A GCRE score based on the GCRE signature consisted of 50 editing sites associated with 29 genes, predicting response to chemotherapy with a high accuracy (84%). Of note, patients demonstrating higher editing levels of this panel of sites presented a better overall response. Consistently, gastric cancer cell lines with higher editing levels showed higher chemosensitivity. Applying the GCRE score on TCGA dataset confirmed that responders had significantly higher levels of editing in advanced gastric cancer. Overall, this newly defined GCRE signature reliably stratifies patients with advanced gastric cancer and predicts response from chemotherapy. Significance: This study describes a novel A-to-I RNA editing signature as a prognostic and predictive biomarker in advanced gastric cancer, providing a new tool to improve patient stratification and response to therapy.

Purpose: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel laparoscopic, intraperitoneal chemotherapy delivery technique aiming to improve drug distribution and tissue penetration to treat peritoneal metastases. Thus far, PIPAC oxaliplatin is conducted at an arbitrary dose of 92 mg/m2. We conducted a phase I study to establish safety and tolerability. Patients and Methods: We used a 3+3 dose-escalation design of PIPAC oxaliplatin for patients with peritoneal metastases from gastrointestinal tumors, after failure of at least first-line chemotherapy. Dose levels were planned at 45, 60, 90, and 120 mg/m2. Results: This study included 16 patients with 24 PIPAC procedures (8 gastric; 5 colorectal; and 1 gallbladder, pancreas, and appendix cancer each). Median age and peritoneal cancer index (PCI) score were 62 years and 17, respectively. Two patients developed pancreatitis (grade 2 and 3) at 45 mg/m2, necessitating cohort expansion. Another patient developed grade 2 pancreatitis at 90 mg/m2. There were no other dose-limiting toxicities, and the highest-dose cohort (120 mg/m2) tolerated PIPAC well. Pharmacokinetic analyses demonstrated good linearity between dose and maximum concentration (r2 = 0.95) and AUC (r2 = 0.99). On the basis of RECIST, 62.5% and 50% had stable disease after one and two PIPAC procedures, respectively. A total of 8 patients underwent two PIPAC procedures, with improvement of median PCI and peritoneal regression grade score from 15 to 12 and 2.5 to 2.0, respectively. Conclusions: The recommended phase II dose is 120 mg/m2. Future studies should further delineate the efficacy and role of PIPAC oxaliplatin for peritoneal metastases. See related commentary by de Jong et al., p. 1830

Background The role of perioperative or neoadjuvant chemotherapy for locally advanced colon cancer is unclear. Emerging evidence such as the FOXTROT trial is challenging the conventional norm of upfront operation for these patients. However, these trials have yet to reach statistical significance. Methods MEDLINE, Embase, Cochrane Library, China Knowledge Resource Integrated Database (CNKI) and ClinicalTrials.gov were searched. Randomized controlled trials (RCTs) and observational studies of patients with locally advanced colon cancer were included. The intervention arm was neoadjuvant chemotherapies while the comparator arm was adjuvant chemotherapies. Studies which reported outcomes of interests included overall survival, disease-free survival, R0 resection rate, perioperative complications and adverse effects of chemotherapy were chosen. Results We identified five eligible randomized trials and two observational studies, including 29,504 patients. Neoadjuvant therapies exhibited statistically significant improvement in overall survival [hazard ratio (HR) =0.76, 95% confidence interval (CI): 0.65-0.89, P=0.0005], and disease-free survival (HR =0.74, 95% CI: 0.58-0.95, P=0.02). R0 resection rate fell slightly short of significance [odds ratio (OR) =1.86, 95% CI: 0.95-3.62, P=0.07]. Risk of peri-operative complications did not differ between groups when examining abdominal infection [risk ratio (RR) =1.14, 95% CI: 0.59-2.18, P=0.70] and anastomotic leakage (RR =0.83, 95% CI: 0.53-1.31, P=0.42). No statistical differences in complications from chemotherapy were reported. Conclusions This meta-analysis highlights the potential survival benefit of neoadjuvant chemotherapy compared to adjuvant chemotherapy for locally advanced colon cancer, without an increase in surgical morbidity. Neoadjuvant or perioperative approaches may be considered an alternative to upfront surgery followed by chemotherapy for locally advanced colon cancer.

Metformin may have a role in reducing the incidence of colorectal cancer (CRC) and improving survival outcome. This meta-analysis explored the effect of metformin use on colorectal adenoma and cancer incidence, and colorectal oncological outcomes. A database search was conducted on Medline, Embase and CNKI for studies comparing metformin vs. non-metformin users, metformin users vs. non-diabetics and metformin users vs. diabetics with diet-only treatment. Meta-analysis was done with DerSimonian and Laird with risk ratios (RR), and hazard ratios (HR) for survival outcomes. We included 58 studies and summarized incidences of colorectal adenoma and cancer, as well as cancer survival outcomes. Metformin users had a significant lower incidence of colorectal adenoma (RR 0.77, CI 0.67–0.88, p

Platinum-based therapeutics are used to manage many forms of cancer, but frequently result in peripheral neuropathy. Currently, the only option available to attenuate chemotherapy-induced neuropathy is to limit or discontinue this treatment. Sphingosine 1-phosphate (S1P) is a lipid-based signaling molecule involved in neuroinflammatory processes by interacting with its five cognate receptors: S1P1–5. In this study, using a combination of drug pharmacodynamic analysis in human study participants, disease modeling in rodents, and cell-based assays, we examined whether S1P signaling may represent a potential target in the treatment of chemotherapy-induced neuropathy. To this end, we first investigated the effects of platinum-based drugs on plasma S1P levels in human cancer patients. Our analysis revealed that oxaliplatin treatment specifically increases one S1P species, d16:1 S1P, in these patients. Although d16:1 S1P is an S1P2 agonist, it has lower potency than the most abundant S1P species (d18:1 S1P). Therefore, as d16:1 S1P concentration increases, it is likely to disproportionately activate proinflammatory S1P1 signaling, shifting the balance away from S1P2. We further show that a selective S1P2 agonist, CYM-5478, reduces allodynia in a rat model of cisplatin-induced neuropathy and attenuates the associated inflammatory processes in the dorsal root ganglia, likely by activating stress-response proteins, including ATF3 and HO-1. Cumulatively, the findings of our study suggest that the development of a specific S1P2 agonist may represent a promising therapeutic approach for the management of chemotherapy-induced neuropathy.

Purpose Severe peripheral neuropathy is a common dose-limiting toxicity of taxane chemotherapy, with no effective treatment. Frozen gloves have shown to reduce the severity of neuropathy in several studies but comes with the incidence of undesired side effects such as cold intolerance and frostbite in extreme cases. A device with thermoregulatory features which can safely deliver tolerable amounts of cooling while ensuring efficacy is required to overcome the deficiencies of frozen gloves. The role of continuous-flow cooling in prevention of neurotoxicity caused by paclitaxel has been previously described. This study hypothesized that cryocompression (addition of dynamic pressure to cooling) may allow for delivery of lower temperatures with similar tolerance and potentially improve efficacy. Method A proof-of-concept study was conducted in cancer patients receiving taxane chemotherapy. Each subject underwent four-limb cryocompression with each chemotherapy infusion (three hours) for a maximum of 12 cycles. Cryocompression was administered at 16 °C and cyclic pressure (5–15 mmHg). Skin surface temperature and tolerance scores were recorded. Neuropathy was assessed using clinician-graded peripheral sensory neuropathy scores, total neuropathy score (TNS) and nerve conduction studies (NCS) conducted before (NCSpre), after completion (NCSpost) and 3 months post-chemotherapy (NCS3m). Results were retrospectively compared with patients who underwent paclitaxel chemotherapy along with continuous-flow cooling and controls with no hypothermia. Results In total, 13 patients underwent 142 cycles of cryocompression concomitant with chemotherapy. Limb hypothermia was well tolerated, and only 1 out of 13 patients required an intra-cycle temperature increase, with no early termination of cryocompression in any subject. Mean skin temperature reduction of 3.8 ± 1.7 °C was achieved. Cryocompression demonstrated significantly greater skin temperature reductions compared to continuous-flow cooling and control (p < 0.0001). None of the patients experienced severe neuropathy (clinician-assessed neuropathy scores of grade 2 or higher). NCS analysis showed preservation of motor amplitudes at NCS3m in subjects who underwent cryocompression, compared to the controls who showed significant deterioration (NCS3m cryocompression vs. NCS3m control: ankle stimulation: 8.1 ± 21.4%, p = 0.004; below fibula head stimulation: 12.7 ± 25.6%, p = 0.0008; above fibula head stimulation: 9.4 ± 24.3%, p = 0.002). Cryocompression did not significantly affect taxane-induced changes in sensory nerve amplitudes. Conclusion When compared to continuous-flow cooling, cryocompression permitted delivery of lower temperatures with similar tolerability. The lower skin surface temperatures achieved potentially lead to improved efficacy in neurotoxicity amelioration. Larger studies investigating cryocompression are required to validate these findings.

Background: DNA methylation signatures describing distinct histological subtypes of oesophageal cancer have been reported. We studied DNA methylation in samples from the MRC OE02 phase III trial, which randomised patients with resectable oesophageal cancer to surgery alone (S) or neoadjuvant chemotherapy followed by surgery (CS).Aim: The aim of the study was to identify epigenetic signatures predictive of chemotherapy benefit in patients with oesophageal adenocarcinoma (OAC) from the OE02 trial and validate the findings in an independent cohort.Methods: DNA methylation was analysed using the Illumina GoldenGate platform on surgically resected OAC specimens from patients in the OE02 trial. Cox proportional hazard analysis was performed to select probes predictive of survival in the CS arm. Non-negative matrix factorisation was used to perform clustering and delineate DNA methylation signatures. The findings were validated in an independent cohort of patients with gastroesophageal adenocarcinoma treated with neoadjuvant chemotherapy.Results: A total of 229 patients with OAC were analysed from the OE02 trial (118 in the CS arm and 111 in the S arm). There was no difference in DNA methylation status between the CS and S arms. A metagene signature was created by dichotomising samples into two clusters. In cluster 1, patients in the CS arm had significant overall survival (OS) benefit (median OS CS: 931 days vs. S: 536 days [HR: 1.54, P = 0.031]). In cluster 2, patients in the CS arm had similar (or worse) OS compared with patients in the S arm (CS: 348 days vs. S: 472 days [HR: 0.70, P = 0.1], and test of interaction was significant (p = 0.005). In the validation cohort (n = 13), there was no difference in DNA methylation status in paired pre- and post-treatment samples. When the epigenetic signature was applied, cluster 1 samples had better OS (median OS, cluster 1: 1174 days vs. cluster 2: 392 days, HR: 3.47, p = 0.059)Conclusions: This is the first and largest study of DNA methylation in patients with OAC uniformly treated in a randomised phase III trial. We identified an epigenetic signature that may serve as a predictive biomarker for chemotherapy benefit in OAC. (C) 2019 Elsevier Ltd. All rights reserved.

PurposeTaxanes are widely used in gynecological cancer therapy, however, taxane-induced peripheral neuropathy (TIPN) limits chemotherapy dose and reduces patients’ quality of life. As a safe and convenient intervention, cryotherapy has been recommended as a promising intervention in the recent clinical guidelines for the prevention of TIPN. Although there are a considerable number of studies which explored the use of cryotherapy in preventing chemotherapy-induced peripheral neuropathy (CIPN), there is insufficient large-scale clinical evidence. We performed a meta-analysis on the current available evidence to examine whether cryotherapy can prevent TIPN in cancer patients receiving taxanes.MethodsWe searched databases including PubMed, Embase, and Cochrane from inception to August 3, 2021 for eligible trials. Clinical trials that examined the efficacy of cryotherapy for prevention of TIPN were included. The primary outcome was the incidence of TIPN, and secondary outcomes were incidence of taxane dose reduction and changes in nerve conduction studies. The meta-analysis software (RevMan 5.3) was used to analyze the data.ResultsWe analyzed 2250 patients from 9 trials. Assessments using the Common Terminology Criteria for Adverse Events (CTCAE) score showed that cryotherapy could significantly reduce the incidence of motor and sensory neuropathy of grade≥2 (sensory: RR 0.65, 95%CI 0.56 to 0.75, pp=0.04). When evaluated using the Patient Neuropathy Questionnaire (PNQ), cryotherapy demonstrated significant reduction in the incidence of sensory neuropathy (RR 0.11, 95% CI 0.04 to 0.31], pp=0.28). Cryotherapy was associated with reduced incidences of taxane dose reduction due to TIPN (RR 0.48, 95% CI [0.24, 0.95], p=0.04) and had potential to preserve motor nerves.ConclusionsCryotherapy is likely to prevent TIPN in patients receiving taxanes. High quality and sufficient amount of evidence is warranted.

Introduction: Oncologists have traditionally administered the maximum tolerated doses of drugs in chemotherapy. However, these toxicity-guided doses may lead to suboptimal efficacy. CURATE.AI is an indication-agnostic, mechanism-independent and efficacy-driven personalised dosing platform that may offer a more optimal solution. While CURATE.AI has already been applied in a variety of clinical settings, there are no prior randomised controlled trials (RCTs) on CURATE.AI-guided chemotherapy dosing for solid tumours. Therefore, we aim to assess the technical and logistical feasibility of a future RCT for CURATE.AI-guided solid tumour chemotherapy dosing. We will also collect exploratory data on efficacy and toxicity, which will inform RCT power calculations.Methods and analysis: This is an open-label, single-arm, two-centre, prospective pilot clinical trial, recruiting adults with metastatic solid tumours and raised baseline tumour marker levels who are planned for palliative-intent, capecitabine-based chemotherapy. As CURATE.AI is a small data platform, it will guide drug dosing for each participant based only on their own tumour marker levels and drug doses as input data. The primary outcome is the proportion of participants in whom CURATE.AI is successfully applied to provide efficacy-driven personalised dosing, as judged based on predefined considerations. Secondary outcomes include the timeliness of dose recommendations, participant and physician adherence to CURATE.AI-recommended doses, and the proportion of clinically significant dose changes. We aim to initially enrol 10 participants from two hospitals in Singapore, perform an interim analysis, and consider either cohort expansion or an RCT. Recruitment began in August 2020. This pilot clinical trial will provide key data for a future RCT of CURATE.AI-guided personalised dosing for precision oncology.Ethics and dissemination: The National Healthcare Group (NHG) Domain Specific Review Board has granted ethical approval for this study (DSRB 2020/00334). We will distribute our findings at scientific conferences and publish them in peer-reviewed journals.Trial registration number: NCT04522284

HSP90 is involved in stability and function of cancer-related proteins. This study was conducted to define the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of TAS-116, a novel class, orally available, highly selective inhibitor of HSP90. Patients with advanced solid tumors received TAS-116 orally once daily (QD, step 1) or every other day (QOD, step 2) in 21-day cycles. Each step comprised a dose escalation phase to determine MTD and an expansion phase at the MTD. In the dose escalation phase, an accelerated dose-titration design and a “3+3” design were used. Sixty-one patients were enrolled in Japan and the United Kingdom. MTD was determined to be 107.5 mg/m2/day for QD, and 210.7 mg/m2/day for QOD. In the expansion phase of step 1, TAS-116 was administered 5 days on/2 days off per week (QD × 5). The most common treatment-related adverse events included gastrointestinal disorders, creatinine increases, AST increases, ALT increases, and eye disorders. Eye disorders have been reported with HSP90 inhibitors; however, those observed with TAS-116 in the expansion phases were limited to grade 1. The systemic exposure of TAS-116 increased dose-proportionally with QD and QOD regimens. Two patients with non–small cell lung cancer and one patient with gastrointestinal stromal tumor (GIST) achieved a confirmed partial response. TAS-116 had an acceptable safety profile with some antitumor activity, supporting further development of this HSP90 inhibitor. This is a result from a first-in-human study, in which the HSP90 inhibitor TAS-116 demonstrated preliminary antitumor efficacy in patients with advanced solid tumors, including those with heavily pretreated GIST.

Background Utilization of alternative transcription start sites through alterations in epigenetic promoter regions causes reduced expression of immunogenic N-terminal peptides, which may facilitate immune evasion in early gastric cancer. We hypothesized that tumors with high alternate promoter utilization would be resistant to immune checkpoint inhibition in metastatic gastric cancer. Patients and methods Two cohorts of patients with metastatic gastric cancer treated with immunotherapy were analyzed. The first cohort (N = 24) included patients treated with either nivolumab or pembrolizumab. Alternate promoter utilization was measured using the NanoString® (NanoString Technologies, Seattle, WA, USA) platform on archival tissue samples. The second cohort was a phase II clinical trial of patients uniformly treated with pembrolizumab (N = 37). Fresh tumor biopsies were obtained, and transcriptomic analysis was carried out on RNAseq data. Alternate promoter utilization was correlated to T-cell cytolytic activity, objective response rate and survival. Results In the first cohort 8 of 24 (33%) tumors were identified to have high alternate promoter utilization (APhigh), and this was used to define the APhigh tertile of the second cohort (13 APhigh of 37). APhigh tumors exhibited decreased markers of T-cell cytolytic activity and lower response rates (8% versus 42%, P = 0.03). Median progression-free survival was lower in the APhigh group (55 versus 180 days, P = 0.0076). In multivariate analysis, alternative promoter utilization was an independent predictor of immunotherapy survival [hazard ratio 0.29, 95% confidence interval 0.099–0.85, P = 0.024). Analyzing tumoral evolution through paired pre-treatment and post-treatment biopsies, we observed consistent shifts in alternative promoter utilization rate associated with clinical response. Conclusion A substantial proportion of metastatic gastric cancers utilize alternate promoters as a mechanism of immune evasion, and these tumors may be resistant to anti-PD1 immune checkpoint inhibition. Alternate promoter utilization is thus a potential mechanism of resistance to immune checkpoint inhibition, and a novel predictive biomarker for immunotherapy. Trial Registration ClinicalTrials.gov Identifier: NCT#02589496

Background Loss of ataxia telangiectasia mutated (ATM), a key protein regulating DNA repair signaling, has been suggested to increase sensitivity to DNA damaging agents. We conducted a study analyzing the loss of ATM protein expression in colorectal cancer and correlated this with clinical outcomes. Materials and Methods The clinical outcomes data and tumor samples from metastatic colorectal cancer patients referred to the Royal Marsden Hospital Drug Development Unit (United Kingdom) from 2012 to 2016 and providing consent for a molecular characterization study were analyzed. Immunohistochemistry (IHC) slides were assessed by a pathologist for nuclear staining intensity of ATM and semiquantitatively scored. ATM loss was defined as a nuclear H-score of ≤ 10. Results Of 223 colorectal cancer samples, ATM IHC loss was identified in 17 (8%). ATM loss was independent of the RAS and RAF mutational status. ATM loss was associated with superior overall survival after first-line oxaliplatin-based therapy (49 vs. 32 months; hazard ratio [HR], 2.52) but not with irinotecan-based therapy (24 vs. 33 months; HR, 0.72). ATM loss was not prognostic for survival from the diagnosis (50 vs. 44 months; HR, 1.43). Conclusion ATM could be considered a biomarker for the development of novel DNA repair targeting agents and treatment of colorectal cancer.

Background The incidence and clinical significance of electrolyte abnormalities (EAs) in phase I clinical trials are unknown. The objective of this study is to evaluate the incidence and severity of EAs, graded according to CTCAE, v4.03, to identify variables associated with EAs and their prognostic significance in a phase I population. Methods A retrospective chart review was performed of 1088 cases in 82 phase I clinical trials consecutively treated from 2011 to 2015 at the Drug Development Unit of the Royal Marsden Hospital. Cox regression analysis was performed to examine the relationship between overall survival (OS) and baseline characteristics, treating the occurrence of grade III/IV EAs as a time-varying covariate. Results The most common emergent EAs (all grades) were as follows: hyponatraemia 62%, hypokalaemia 40%, hypophosphataemia 32%, hypomagnesaemia 17% and hypocalcaemia 12%. Grade III/IV EAs occurred in 19% of cases. Grade III/IV EAs occurred during the dose-limiting toxicity window in 8.46% of cases. Diarrhoea was associated with hypomagnesaemia at all grades (p, Highlights • Patients who develop grade III/IV electrolyte abnormalities have poorer overall survival. • Hyponatraemia is linked to higher risk of developing other electrolyte abnormalities. • Hypoalbuminaemia is linked to higher risk of developing electrolyte abnormalities.

Purpose: The oxaliplatin plus S-1 and cisplatin plus S-1 regimens are interchangeably used in the management of advanced gastric cancer. The previously reported G-intestinal (G1) and G-diffuse (G2) intrinsic gene expression signatures showed promise for stratifying patients according to their tumor sensitivity to oxaliplatin or cisplatin. Experimental Design: The proof-of-concept, multicenter, open-label phase II “3G” trial was done to prospectively evaluate the feasibility and efficacy of using genomic classifiers to tailor treatment in gastric cancer. Patients’ tumors were classified as “G1” or “G2” using a nearest-prediction template method, or “G3” (unclear assignment) when FDR ≥ 0.05. The first 30 patients in the “G1” cohort were assigned oxaliplatin plus S-1 (SOX) chemotherapy; thereafter, subsequently recruited “G1” patients were treated with cisplatin plus S-1 (SP) chemotherapy. “G2” patients and “G3” patients were treated with SP and SOX chemotherapy, respectively. Results: A total of 48, 21, and 12 patients, respectively, were given “G1,” “G2,” and “G3” genomic assignments. Median turnaround time was 7 days (IQR, 5–9). Response rates were 44.8%, 8.3%, 26.7%, and 55.6% for the “G1-SOX,” “G1-SP,” “G2,” “G3” cohorts, respectively; and was higher in G1 patients treated with SOX compared with SP (P = 0.033). Exploratory analyses using the genomic classifier of Lei and colleagues validated the utility of the metabolic signature as a biomarker for predicting benefit from chemotherapy (log-rank P = 0.004 for PFS), whereas the Asian Cancer Research Group classifier did not demonstrate any predictive value. Conclusions: This bench-to-bedside effort establishes a reasonable turnaround time for gene expression profiling and possible utility of genomic classifiers in gastric cancer treatment stratification. Clin Cancer Res; 24(21); 5272–81. ©2018 AACR.

A dose of 200 mg 3-weekly of pembrolizumab was approved by the Food and Drug Administration (FDA) as treatment for advanced non-small cell lung cancer (NSCLC) without oncogenic drivers. This is despite evidence showing no difference in efficacy with 2 mg/kg. Our study aimed to assess the efficacy of a lower fixed dose of 100 mg, which is closer to 2 mg/kg weight-based dose in an average-sized Asian patient. All patients receiving pembrolizumab for advanced NSCLC from January 2016 to March 2020 in National University Hospital, Singapore, were included in this retrospective observational study. The effect of pembrolizumab 100 mg (Pem100) vs 200 mg (Pem200) upon survival outcomes, toxicity and cost were examined. One hundred fourteen patients received pembrolizumab. Sixty-five (57%) and 49 (43%) received Pem100 and Pem200, respectively. There was no difference in progression-free survival (PFS) and overall survival (OS) between Pem100 vs Pem200 as a single agent (PFS: 6.8 vs 4.2 months, hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.36-1.46, P = .36; 9 month OS: 58% vs 63%, HR 1.08, 95% CI 0.48-2.41, P = .86) and when combined with chemotherapy (9-month PFS: 60% vs 50%, HR0.84, 95% CI 0.34-2.08, P = .71; 9-month OS: 85% vs 58%, HR 0.27, 95% CI 0.062-1.20, P = .09). No significant difference in response rate or ≥G3 immune-related toxicities between Pem100 and Pem200 was observed. A cost minimisation analysis evaluating the degree of cost savings related to drug costs estimated a within study cost saving of SGD4,290,912 and cost saving per patient of SGD39,942 in the Pem100 group. A 100 mg of pembrolizumab appears to be effective with reduction in cost. A randomised trial should be done to investigate a lower dose of pembrolizumab.

Background Malignant pleural mesothelioma (MPM) is traditionally characterized by local destructive spread of the pleura and surrounding tissues. Patient outcomes in MPM with distant metastatic dissemination are lacking. Methods In this retrospective study, we reviewed a cohort of 164 MPM patients referred to a Phase I trials unit, aiming to describe identified metastatic sites, and correlate with clinical outcomes. Results 67% of patients were diagnosed with distant metastatic disease with a high incidence of bone (19%), visceral (14%), contralateral lung (35%) and peritoneal metastases (22%). Peritoneal metastases were more likely in epithelioid versus biphasic/ sarcomatoid MPM (p = 0.015). Overall survival was 23.8 months with no statistical difference in survival between those with distant metastases and those without. Conclusions This report highlights the frequency of distant metastases and encourages further radiological investigations in the presence of symptoms. In particular, given the relatively high incidence of bone metastases, bone imaging should be considered in advanced MPM clinical workflow and trial protocols. The presence of distant metastases does not appear to have prognostic implications under existing treatment paradigms. This cohort of MPM patients gives an indication of patterns of metastatic spread that are likely to become prevalent as prognosis improves with emerging treatment paradigms.

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common dose-limiting side-effect of taxane-based chemotherapy, causing progressive and often irreversible pain/sensitivity in the hands and feet. Prevention/treatments for CIPN are not well-developed and urgently needed. Limb cryocompression during chemotherapy has demonstrated promising early data of preventing/reducing CIPN severity. Currently there are no medical devices available that are dedicated to the specific requirements of CIPN prevention. As part of our ongoing development of a dedicated CIPN-prevention limb cryocompression system, this study documents the design & development of the wearable arm wrap, a central component of the system, from initial concept to a trial-ready prototype. A collaborative and multidisciplinary approach was adopted to address the complex and high-risk nature of this SME (Small Medium Enterprise)-centered medical device design & development process. The complementary collaboration unites multidisciplinary expertise spanning the scope of the project. Alongside the clinical, academic, and design & development expertise, the integration of commercial expertise is imperative to promote the market viability, and ultimate success, of the development. As the global leading experts in scalp cooling specializing in the prevention of chemotherapy-induced alopecia, UK-based SME Paxman Coolers Ltd is optimally positioned to support the commercial and regulatory dimensions. Development and adoption of a novel mixed-methodology (HudPAX) facilitated the integration of evidence-based and user-centered techniques to optimize the design & development approach and ensure integration of all critical design inputs. Alpha prototypes were designed through evidence-based approaches, with data from existing clinical trials utilized to determine the preliminary design inputs, alongside 3D ergonomic data. Investigations utilized computer-aided design, rapid prototyping, additive manufacturing, sketch modeling, and fast ideation. User-based approaches facilitated stakeholder-feedback through expert focus groups, informing further design & development and projecting the design into the next stage, Beta prototyping, for use in large-scale efficacy trials and upscaling manufacturing. This paper demonstrates a novel mixed-methods approach, which promotes cross-sector multidisciplinary collaboration, to address the complex multi-layered challenges posed by an early-stage medical device design & development process.

ObjectiveEndoscopic mucosal biopsies of primary gastric cancers (GCs) are used to guide diagnosis, biomarker testing and treatment. Spatial intratumoural heterogeneity (ITH) may influence biopsy-derived information. We aimed to study ITH of primary GCs and matched lymph node metastasis (LNmet).DesignGC resection samples were annotated to identify primary tumour superficial (PTsup), primary tumour deep (PTdeep) and LNmet subregions. For each subregion, we determined (1) transcriptomic profiles (NanoString ‘PanCancer Progression Panel’, 770 genes); (2) next-generation sequencing (NGS, 225 gastrointestinal cancer-related genes); (3) DNA copy number profiles by multiplex ligation-dependent probe amplification (MLPA, 16 genes); and (4) histomorphological phenotypes.ResultsNanoString profiling of 64 GCs revealed no differences between PTsup1 and PTsup2, while 43% of genes were differentially expressed between PTsup versus PTdeep and 38% in PTsup versus LNmet. Only 16% of genes were differently expressed between PTdeep and LNmet. Several genes with therapeutic potential (eg IGF1, PIK3CD and TGFB1) were overexpressed in LNmet and PTdeep compared with PTsup. NGS data revealed orthogonal support of NanoString results with 40% mutations present in PTdeep and/or LNmet, but not in PTsup. Conversely, only 6% of mutations were present in PTsup and were absent in PTdeep and LNmet. MLPA demonstrated significant ITH between subregions and progressive genomic changes from PTsup to PTdeep/LNmet.ConclusionIn GC, regional lymph node metastases are likely to originate from deeper subregions of the primary tumour. Future clinical trials of novel targeted therapies must consider assessment of deeper subregions of the primary tumour and/or metastases as several therapeutically relevant genes are only mutated, overexpressed or amplified in these regions.

BackgroundWe previously reported that low-dose, short-course sunitinib prior to neoadjuvant doxorubicin-cyclophosphamide (AC) normalised tumour vasculature and improved perfusion, but resulted in neutropenia and delayed subsequent cycles in breast cancer patients. This study combined sunitinib with docetaxel, which has an earlier neutrophil nadir than AC.MethodsPatients with advanced solid cancers were randomized 1:1 to 3-weekly docetaxel 75 mg/m2, with or without sunitinib 12.5 mg daily for 7 days prior to docetaxel, stratified by primary tumour site. Primary endpoints were objective-response (ORR:CR + PR) and clinical-benefit rate (CBR:CR + PR + SD); secondary endpoints were toxicity and progression-free-survival (PFS).ResultsWe enrolled 68 patients from 2 study sites; 33 received docetaxel-sunitinib and 35 docetaxel alone, with 33 breast, 25 lung and 10 patients with other cancers.There was no difference in ORR (30.3% vs 28.6%,p = 0.432, odds-ratio [OR] 1.10, 95% CI 0.38–3.18); CBR was lower in the docetaxel-sunitinib arm (48.5% vs 71.4%,p = 0.027 OR 0.37, 95% CI 0.14–1.01). Median PFS was shorter in the docetaxel-sunitinib arm (2.9 vs 4.9 months, hazard-ratio [HR] 2.00, 95% CI 1.15–3.48,p = 0.014) overall, as well as in breast (4.2 vs 5.6 months,p = 0.048) and other cancers (2.0 vs 5.3 months,p = 0.009), but not in lung cancers (2.9 vs 4.1 months,p = 0.597). Median OS was similar in both arms overall (9.9 vs 10.5 months, HR 0.92, 95% CI 0.51–1.67,p = 0.789), and in the breast (18.9 vs 25.8 months,p = 0.354), lung (7.0 vs 6.7 months,p = 0.970) and other cancers (4.5 vs 8.8 months,p = 0.449) subgroups.Grade 3/4 haematological toxicities were lower with docetaxel-sunitinib (18.2% vs 34.3%,p = 0.132), attributed to greater discretionary use of prophylactic G-CSF (90.9% vs 63.0%,p = 0.024). Grade 3/4 non-haematological toxicities were similar (12.1% vs 14.3%,p = 0.792).ConclusionsThe addition of sunitinib to docetaxel was well-tolerated but did not improve outcomes. The possible negative impact in metastatic breast cancer patients is contrary to results of adding sunitinib to neoadjuvant AC. These negative results suggest that the intermittent administration of sunitinib in the current dose and schedule with docetaxel in advanced solid tumours, particularly breast cancers, is not beneficial.Trial registrationThe study was registered (NCT01803503) prospectively on clinicaltrials.gov on 4th March 2013.

BackgroundDifferentiating between malignant and normal cells within tissue samples is vital for molecular profiling of cancer using advances in genomics and transcriptomics. Cell-surface markers of tumour–normal discrimination have additional value in terms of translatability to diagnostic and therapeutic strategies. In gastric cancer (GC), previous studies have identified individual genes or proteins that are upregulated in cancer. However, a systematic analysis of cell-surface markers and development of a composite panel involving multiple candidates to differentiate tumour from normal has not been previously reported.MethodsWhole transcriptome sequencing (WTS) of GC and matched normal samples from the Singapore Gastric Cancer Consortium (SGCC) was used as a discovery cohort to identify upregulated putative cell-surface proteins. Matched WTS data from the The Cancer Genome Atlas (TCGA) was used as a validation cohort. Promising candidates from this analysis were validated orthogonally using multispectral immunohistochemistry (mIHC) with automated quantitative analysis using the Vectra platform. mIHC was performed on a tissue microarray containing matched normal, marginal and tumour tissues. The receiver-operating characteristic (ROC) curves were analysed to identify markers with the highest diagnostic validity independently and in combination.ResultsAnalysis of putative membrane protein transcripts from the SGCC discovery cohort WTS data (n=15 matched tumour and normal pairs) identified several differentially and highly expressed candidates in tumour compared with normal tissues. After validation with TCGA data (n=29 matched tumour and normal pairs), the following proteins were selected for mIHC analysis: CEACAM5, CEACAM6, CLDN4, CLDN7, and EpCAM. These were compared with established glycoprotein markers in GC, namely CA19-9 and CA72-4. Individual ROC curves yielded the best performance for CEACAM5 (area under the ROC curve (AUC)=0.80), CEACAM6 (AUC=0.82), EpCAM (AUC=0.83), and CA72-4 (AUC=0.76). Combined multiplexed imaging of these four markers revealed improved specificity and sensitivity for detection of tumour from normal tissue (AUC of 4-plex=0.91).ConclusionCEAMCAM5, CEACAM6, EpCAM, and CA72-4 form a versatile set of markers for robust discrimination of GC from adjacent normal tissue. As cell-surface markers, they are compatible with both IHC and live imaging approaches. These candidates may be exploited to improve automated identification of tumour tissue in GC.

Background The aim of this study was to evaluate the psychometric properties of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group—Neurotoxicity (FACT/GOG-Ntx) subscale in a longitudinal study of cancer patients treated with chemotherapy. Methods Patients were assessed with the FACT/GOG-Ntx subscale, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy Scale 20 (EORTC QLQ-CIPN20), National Cancer Institute -Common Terminology Criteria for Adverse Events (NCI-CTCAE), and light touch test using 10 g monofilament for up to ten assessment points from baseline (prior to initiation of first chemotherapy), after the end of each cycle (up to 6 cycles, 3 weeks per cycle), and at 6, 9, and 12 months after starting chemotherapy. Psychometric analyses included internal consistency reliability, convergent validity, factorial validity, sensitivity to change and responsiveness (minimal clinically important difference, MCID). Results Cronbach’s alpha coefficients of the FACT/GOG-Ntx subscale were 0.82–0.89 across assessment points. The subscale strongly correlated with the EORTC QLQ-CIPN20 (r = 0.79–0.93) but low-to-moderately correlated with the NCI-CTCAE sensory (rs = 0.23–0.45) and motor items (rs = 0.15–0.50) as well as the monofilament test (rs = 0.23–0.47). The hypothesized 4-factor structure of the FACT/GOG-Ntx subscale was not confirmed at assessment points (χ2/df = 2.26–8.50; all P r = 0.17–0.37). The MCIDs were between 1.38 and 3.68. Conclusion The FACT/GOG-Ntx subscale has satisfactory reliability, validity, sensitivity to change and responsiveness to evaluate CIPN in cancer patients. Future research is needed to explore the factorial structure of the FACT/GOG-Ntx subscale as the published four-factor structure was not supported in this study.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting adverse effect of neurotoxic chemotherapeutic agents. Recent studies have suggested clinical utility of limb hypothermia in reducing CIPN. However, conventional cooling methods such as ice packs are unable to provide thermoregulated cooling and cause frostbites. Cooling modalities offering thermoregulation have been developed for sports injury and orthopaedic indications, but not explored for preventing CIPN. This study aims to determine the safety, tolerability and optimal parameters of three cooling modalities for delivery of limb hypothermia in healthy subjects, prior to testing in cancer patients for prevention of CIPN. Healthy subjects underwent limb hypothermia by either: continuous-flow cooling, cryocompression or frozen gloves. Skin temperatures and tolerance scores were monitored. Overall, 58 subjects underwent limb hypothermia. No adverse events were observed barring transient erythema. Both continuous-flow cooling and cryocompression are feasible, safe and tolerable methods for delivery of limb hypothermia. Cryocompression achieved lower skin temperatures than continuous-flow cooling with similar safety profiles. Frozen gloves were minimally tolerated. Cryocompression may provide greater efficacy in preventing CIPN, with clinical trials currently underway.

Purpose: Induction cisplatin and gemcitabine chemotherapy is a standard treatment for locally advanced nasopharyngeal carcinoma (NPC). Inhibition of VEGF axis has been shown to promote maturation of microvasculature and improve perfusion. We conducted a four-arm study to assess the effect of two doses of either sunitinib or bevacizumab with chemotherapy in NPC. Patients and Methods: Patients with treatment-naïve locally advanced NPC were treated with three cycles of 3-weekly cisplatin and gemcitabine preceded by 1 week of anti-VEGF therapy for each cycle, followed by standard concurrent chemoradiation: arm A patients received 7 days of 12.5 mg/day sunitinib; arm B 7 days of 25 mg/day sunitinib; arm C bevacizumab 7.5 mg/kg infusion; arm D bevacizumab 2.5 mg/kg infusion. Patients with metastatic NPC were treated with up to six cycles of similar treatment without concurrent chemoradiation. Results: Complete metabolic response (mCR) by whole body 18FDG PET was highest in arm C (significant difference in four groups Fisher exact test P = 0.001; type 1 error = 0.05), with 42% mCR (95% confidence interval, 18–67) and 3-year relapse-free survival of 88% in patients with locally advanced NPC. Significant increase in pericyte coverage signifying microvascular maturation and increased immune cell infiltration was observed in posttreatment tumor biopsies in Arm C. Myelosuppression was more profound in sunitinib containing arms, and tolerability was established in arm C where hypertension was the most significant toxicity. Conclusions: Bevacizumab 7.5 mg/kg with cisplatin and gemcitabine was well tolerated. Promising tumor response was observed and supported mechanistically by positive effects on tumor perfusion and immune cell trafficking into the tumor.

Immune checkpoint inhibition has transformed cancer treatment. For gastroesophageal cancer, this class of drugs have demonstrated durable responses and survival benefit in a subgroup of patients, resulting in regulatory approval. However, several recent randomized phase III studies in gastroesophageal cancer have reported negative results, blunting initial enthusiasm. Identification and validation of predictive biomarkers with appropriate patient selection for benefit from immunotherapy is an area of intense research with novel concepts rapidly emerging. In this review we describe the latest immune checkpoint inhibitor trials which have been reported in gastroesophageal cancers with a focus on predictive biomarkers. We also explore novel biomarkers being developed to improve precision oncology for immunotherapy in gastroesophageal cancers.

Purpose: Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies. Patients and Methods: In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy. Results: In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91–603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB (n = 9) included multiple cycles of NK cells (1 × 107/kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 107/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0–12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment. Conclusions: NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is common among cancer patients treated with neurotoxic chemotherapy agents. Better knowledge on symptom clusters of CIPN may help improve symptom management in clinical practice. This study aimed to identify symptom clusters of CIPN and to map their trajectories before initiation of chemotherapy to 12-month follow-up. Methods A secondary analysis of a longitudinal dataset was conducted using principal component approach. The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaires Core 30 and CIPN 20 were used to measure symptom clusters of CIPN in patients with mixed cancer diagnosis across 10 time points over 12 months. Results Sample size in each assessment point ranged from 118 to 343 participants. Four CIPN symptom clusters were identified, including a clear sensory neuropathy symptom cluster, a mixed motor-sensory neuropathy symptom cluster, a mixed sensorimotor neuropathy symptom cluster, and a less clear autonomic neuropathy symptom cluster. The core symptoms in each symptom cluster were mostly stable while the secondary symptoms changed over time. Conclusions The analysis suggests that CIPN is predominantly a sensory neuropathy with no evidence of a pure motor dysfunction but with mixed motor-related and autonomic changes accompanying sensory dysfunctions over time. Future symptom management strategies can be designed based on the morphology of CIPN.

Background We conducted a phase I/Ib, open-label, single-arm trial to assess the safety, tolerability and optimal scheduling regimen of OTSGC-A24 cancer vaccine in patients with advanced gastric cancer. Methods Patients with advanced gastric cancer with HLA-A*24:02 haplotype were included in this study. OTSGC-A24 was administered at 1 mg in 3-weekly (3w), 2-weekly (2w), and weekly (1w) cohorts to evaluate the safety, immunological response and schedule. Based on the highest specific cytotoxic T lymphocyte (CTL) induction rate at 4 weeks, using the ELISPOT test, cohorts were expanded to define the optimal dosing schedule for OTSGC-A24. Results In this study, 24 advanced gastric cancer patients with HLA-A*24:02 haplotype were enrolled and treated in 3 cohorts (3w cohort: 3; 2w cohort: 11 and 1w cohort: 10 patients). The most common adverse events were decreased appetite (29%), diarrhea (21%), myalgia (25%). The most common treatment-related adverse event was injection site erythema (25%). No dose-limiting toxicities were observed in any cohort and OTSGC-A24 was well tolerated. Positive CTL responses after vaccination were observed in 15 patients (75%) at 4 weeks: 3w cohort (33%), 2w cohort (88%), 1w cohort (78%). At 12 weeks, 18 patients had responded (90%); 3w cohort (100%), 2w cohort (100%), 1w cohort (78%). The best radiological was stable disease (40%). Median progression free survival was 1.7 months (95% CI: 1.4 to 3.5) and median overall survival was 5.7 months (95% CI 3.8 to 8.6). Conclusions OTSGC-A24 combined peptide cancer vaccine was well tolerated. Significant responses in CTL were observed and the recommended phase 2 dose is 1 mg OTSGC-A24 sub-cutaneous, every 2 weeks. Although no radiological response was observed, a respectable overall survival was achieved, consistent with other immunotherapy agents being investigated in gastric cancer. Trial registration ClinicalTrials.gov Identifier: NCT01227772, Date registered: 21 Oct 2010.

Background: Faced with a trade-off between efficacy and toxicity, oncologists have conventionally administered the maximum tolerated doses in chemotherapy on an assumption that higher doses increase efficacy. However, multiple studies have shown that this method of toxicity-guided dosing may result in more frequent toxicities and potentially suboptimal efficacy. With the advent of artificial intelligence (AI), personalized dosing in chemotherapy may be considered to optimize patient care. CURATE.AI is an efficacy-driven, indication-agnostic and mechanism-independent personalized dosing platform that may offer an optimal solution. In contrast to traditional AI approaches based on massive volumes of population data, CURATE.AI requires only the individual patient's medical profile for dose recommendations. Based on the observation that the relationship between a drug dose and a phenotypic response in a human system can be modelled by a dynamic quadratic surface, CURATE.AI continually guides dosing throughout the treatment duration to optimize efficacy. While CURATE.AI has been used in various clinical settings, there are no prior randomized controlled trials (RCTs) on CURATE.AI-guided chemotherapy dosing for solid tumors. Therefore, we are conducting a pilot study to assess the technical and logistical feasibility of an RCT for CURATE.AI-guided solid tumor chemotherapy dosing. We aim to collect exploratory data on efficacy and toxicity, and on the use of longitudinal blood tumor marker measurements, including ctDNA, to inform dose guidance decision. Methods: PRECISE is an open-label, single-arm, multi-centre, prospective pilot clinical trial on using CURATE.AI to achieve personalized, efficacy-driven and dynamically optimized chemotherapy dosing for solid tumors (NCT04522284). Adults with metastatic solid tumors and raised baseline tumor marker levels who are planned for palliative-intent, capecitabine-based chemotherapy will be recruited. CURATE.AI will guide drug dosing for each participant based only on their own tumor marker levels and drug doses as input data. The primary outcome is the proportion of participants in whom CURATE.AI is successfully applied. Secondary outcomes include the timeliness of dose recommendations, participant and physician adherence to CURATE.AI-recommended doses, and the proportion of clinically significant dose changes. As an exploratory outcome, we will analyze the utility of tumor markers including CEA, CA19-9 and ctDNA in high frequency serial measurements. We aim to initially enroll 10 participants from 2 hospitals in Singapore, perform an interim analysis, and consider either cohort expansion or a RCT based on initial pilot data. Recruitment of patients began in August 2020. As of December 2020, 2 participants have been enrolled with recruitment planned for 1 year. Citation Format: Chong Boon Teo, Benjamin Kye Jyn Tan, Xavier Tadeo, Siyu Peng, Hazel Pei Lin Soh, Sherry De Xuan Du, Vilianty Wen Ya Luo, Aishwarya Bandla, Raghav Sundar, Dean Ho, Theodore Kee, Agata Blasiak. Personalized, rational, efficacy-driven chemotherapy dosing via an artificial intelligence system (PRECISE): A protocol for the PRECISE CURATE.AI pilot clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT211.

DNA damage occurs continually through various intrinsic and extrinsic mechanisms such as ultraviolet radiation, smoking, reactive oxygen species, and errors during replication. The cellular DNA damage response (DDR) comprises signaling networks that regulate a spectrum of processes, including cell cycle progression, which enable DNA repair to occur. Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia mutated and rad3-related (ATR) kinase are 2 key regulators of the DDR cell cycle checkpoints. ATR plays an essential role in the repair of replication-associated DNA damage, while ATM is activated by DNA double-strand breaks. The investigation of cell cycle checkpoint signaling through ATR and ATM, as well as the relevant pathways involved in oncogenesis and cancer progression, has led to the discovery and development of potent and selective ATR inhibitors (ATRi). Preclinical data have demonstrated that ATR inhibition leads to tumor synthetic lethality in specific molecular contexts, and it exhibits synergy in combination with different antitumor therapies, including chemotherapy, radiotherapy, and poly(ADP-ribose) polymerase inhibitors. ATRi are now being assessed in early-phase clinical trials as single agents and in combinatorial regimens, including platinum and other chemotherapies, radiotherapy, poly(ADP-ribose) polymerase inhibitors, and immune checkpoint inhibitors. This article details the preclinical biology leading to the discovery and development of novel ATRi and discusses the rationale for monotherapy and combination antitumor strategies. We focus on the clinical development of ATRi and discuss the progress made in identifying putative predictive biomarkers of response for patient selection, such as p53, ATM, ARID1A, and other DDR aberrations.

Non-small-cell lung cancer (NSCLC) remains a significant global health challenge and the leading cause of cancer-related mortality. The traditional 'one-size-fits-all' treatment approach has now evolved into one that involves personalized strategies based on histological and molecular subtypes. The molecular era has revolutionized the treatment of patients harboring epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and ROS1 gene aberrations. In the appropriately selected population, anti-tumor agents against these molecular targets can significantly improve progression-free survival. However, the emergence of acquired resistance is inevitable. Novel potent compounds with much improved and rational selectivity profiles, such as third-generation EGFR T790M resistance mutation-specific inhibitors, have been developed and added to the NSCLC armamentarium. To date, attempts to overcome resistance bypass pathways through downstream signaling blockade has had limited success. Furthermore, the majority of patients still do not harbor known driver genetic or epigenetic alterations and/or have no new available treatment options, with chemotherapy remaining their standard of care. Several potentially actionable driver aberrations have recently been identified, with the early clinical development of multiple inhibitors against these promising targets currently in progress. The advent of immune checkpoint inhibitors has led to significant benefit for advanced NSCLC patients with durable responses observed. Further interrogation of the underlying biology of NSCLC, coupled with modern clinical trial designs, is now required to develop novel targeted therapeutics rationally matched with predictive biomarkers of response, so as to further advance NSCLC therapeutics through the next decade.

The field of immuno-oncology has witnessed unprecedented success in recent years, with several PD=1 and PD-L1 inhibitors obtaining US FDA registration and breakthrough drug therapy designation in multiple tumor types. Despite its clear efficacy in certain cancers, treatment with these agents carries a risk of immune-related toxicities and substantial financial burden. It is, therefore, critical to identify patients likely to benefit from such immunotherapies and develop strategies to differentiate responders from nonresponders early during treatment. Here we discuss the development of predictive and treatment response biomarkers for immune checkpoint inhibitors. We first examine the role of PD-L1 expression, the most extensively studied predictive biomarker of response, and further discuss emerging putative predictive biomarkers. We also detail challenges faced in the development of response assessments for immunotherapeutics and propose other biomarkers that may be useful as surrogate intermediate end points of response.

Summary: Gastroesophageal adenocarcinoma (GEA) comprises a myriad of distinct subtypes with significant interpatient, intrapatient, and intratumor heterogeneity. Strategies for tackling molecular heterogeneity will be essential for the success of GEA precision oncology—in this regard, blood-based “liquid biopsies” may provide broader views of the real-time genomic landscape of this disease, identifying actionable biomarkers and monitoring therapy resistance. Cancer Discov; 8(1); 14–6. ©2018 AACR. See related article by Pectasides et al., p. 37. See related article by Janjigian et al., p. 49.

Author(s): Molassiotis, Alex; Cheng, Hui Lin; Leung, Kwun To; Li, Yu Chung; Wong, Kam Hung; Au, Joseph Siu Kie; Sundar, Raghav; Chan, Alexandre; Ng, Terrence Rong De; Suen, Lorna KP; Chan, Choi Wan; Yorke, Janelle; Lopez, Violeta | Abstract: BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a significant and difficult to manage side effect of neurotoxic chemotherapies.nSeveral risk factors for CIPN have been identified to date, but inconsistencies and methodological limitations exist in past research. Also, a limited number of potential risk factors has been investigated in the past.AimThe objective of this study was to assess the relative contribution of a wider range of risk factors in the development of CIPN.MethodsThis analysis used the 6-month data after starting chemotherapy from a larger prospective observational study on CIPN risk, prevalence, and quality of life. Patients were assessed at recruitment for possible CIPN risk factors, including prior history of neuropathies, current/past infectious diseases; neurotoxic medication history; personal and treatment characteristics; smoking history, alcohol use, and vegetable/fruit intake. Neuropathy was assessed at 6-months after starting chemotherapy with the neuropathy (motor/sensory) items of the NCI-CTCAE scale and the WHO criterion for neuropathy. Data on symptom burden were also collected.ResultsData were available from 255 patients from three cancer centers in Hong Kong, Singapore, and UK. The use of different scales did not always identify the same predictor variables. Key risk factors in multivariate regression models included older age (highest ORn=n1.08, pnln0.01 with the WHO scale), chemotherapy (platinum-based chemotherapy had ORn=n0.20-0.27 in developing CIPN compared to taxane-based chemotherapy), history of neuropathy (for motor CIPN only, ORn=n8.36, pnln0.01), symptom burden (ORn=n1.06, pnln0.05), number of chemotherapy cycles received (ORn=n1.19-1.24, pnln0.01), and alcohol intake (ORn=n0.32, pnln0.05). In univariate analysis, the use of statins was implicated with CIPN (pn=n0.03-0.04 with different assessments) and diabetes showed a trend (pn=n0.09) in the development of CIPN.ConclusionThis study confirmed the CIPN risk related to certain variables and identified new ones. This knowledge can assist with treatment decisions and patient education.

BackgroundThere are inconsistencies in the literature regarding the prevalence and assessment of chemotherapy-induced peripheral neuropathy (CIPN). This study explored CIPN natural history and its characteristics in patients receiving taxane- and platinum-based chemotherapy.Patients and methodsMulti-country multisite prospective longitudinal observational study. Patients were assessed before commencing and three weekly during chemotherapy for up to six cycles, and at 6,9, and 12 months using clinician-based scales (NCI-CTCAE; WHO-CIPN criterion), objective assessments (cotton wool test;10 g monofilament); patient-reported outcome measures (FACT/GOG-Ntx; EORTC-CIPN20), and Nerve Conduction Studies.ResultsIn total, 343 patients were recruited in the cohort, providing 2399 observations. There was wide variation in CIPN prevalence rates using different assessments (14.2-53.4%). Prevalence of sensory neuropathy (and associated symptom profile) was also different in each type of chemotherapy, with paclitaxel (up to 63%) and oxaliplatin (up to 71.4%) showing the highest CIPN rates in most assessments and a more complex symptom profile. Peak prevalence was around the 6-month assessment (up to 71.4%). Motor neurotoxicity was common, particularly in the docetaxel subgroup (up to 22.1%; detected by NCI-CTCAE). There were relatively moderately-to-low correlations between scales (rs= 0.15,p&nbsp

This is the first study to determine the minimal clinically important difference (MCID) of the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire-CIPN twenty-item scale (EORTC QLQ-CIPN20), a validated instrument designed to elicit cancer patients’ experience of symptoms and functional limitations related to chemotherapy-induced peripheral neuropathy. Cancer patients receiving neurotoxic chemotherapy completed EORTC QLQ-CIPN20 and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-NTX] at baseline, second cycle of chemotherapy (T2, n = 287), and 12 months after chemotherapy (T3, n = 191). Anchor-based approach used the validated FACT/GOG-NTX neurotoxicity (Ntx) subscale to identify optimal MCID cutoff for deterioration. Distribution-based approach used one-third standard deviation (SD), half SD, and one standard error of measurement of the total EORTC QLQ-CIPN20 score. There was a moderate correlation between the change scores of the Ntx subscale and sensory and motor subscales of QLQ-CIPN20 (T2: r = − 0.722, p

Malignant pleural mesothelioma (MPM) is traditionally characterized by local destructive spread of the pleura and surrounding tissues. Patient outcomes in MPM with distant metastatic dissemination are lacking.In this retrospective study, we reviewed a cohort of 164 MPM patients referred to a Phase I trials unit, aiming to describe identified metastatic sites, and correlate with clinical outcomes.67% of patients were diagnosed with distant metastatic disease with a high incidence of bone (19%), visceral (14%), contralateral lung (35%) and peritoneal metastases (22%). Peritoneal metastases were more likely in epithelioid versus biphasic/ sarcomatoid MPM (p = 0.015). Overall survival was 23.8 months with no statistical difference in survival between those with distant metastases and those without.This report highlights the frequency of distant metastases and encourages further radiological investigations in the presence of symptoms. In particular, given the relatively high incidence of bone metastases, bone imaging should be considered in advanced MPM clinical workflow and trial protocols. The presence of distant metastases does not appear to have prognostic implications under existing treatment paradigms. This cohort of MPM patients gives an indication of patterns of metastatic spread that are likely to become prevalent as prognosis improves with emerging treatment paradigms.

247 Background: It is unclear whether prior treatment with ramucirumab (RAM) or RAM plus paclitaxel (PAC), standard second-line treatments for metastatic gastric or gastroesophageal junction cancer (mGC/GEJC), can influence outcomes with third-line chemotherapy in this patient (pt) population (pop). In the phase 3 TAGS trial, FTD/TPI showed a survival benefit vs placebo (PBO) in pts with mGC/GEJC who had received ≥2 prior chemotherapy regimens. Post hoc analyses were performed to assess the impact of prior RAM, PAC or RAM+PAC treatment on the efficacy and safety of FTD/TPI in TAGS. Methods: Pts in the TAGS trial were categorized into 5 subgroups based on prior treatment received as follows: A) RAM (alone or combined with other agents), B) no RAM, C) PAC (but no RAM), D) RAM+PAC (sequentially or in combination) and E) neither PAC nor RAM. While subgroups A and B were prespecified, all other subgroups were identified post hoc. Efficacy (overall survival [OS] and progression-free survival [PFS]) and safety were assessed in these subgroups. Results: In the overall pop (N=507), 33% had received prior RAM (alone/combined); 30% prior RAM+PAC; 27% prior PAC but no RAM; and 40% had received neither PAC nor RAM. As only 3% of all pts received prior RAM but no PAC, that subgroup was not considered in this analysis. FTD/TPI treatment was consistently associated with benefits in OS and PFS vs placebo across all pt subgroups (Table). Among pts randomized to FTD/TPI, OS benefit was similar between pts who received RAM+PAC vs those who received neither (HR, 1.15; 95% CI, 0.84–1.58) and between pts who received PAC (but no RAM) vs those who received neither (HR, 0.91; 95% CI, 0.66–1.25). The FTD/TPI safety profile was consistent across all subgroups, with similar overall incidences of grade ≥3 adverse events (AEs). Minor variations in hematologic toxicities were noted (Table). Conclusions: In the phase 3 TAGS trial, FTD/TPI treatment in the third or later line provided efficacy benefits vs PBO and demonstrated a consistent safety profile in pts with mGC/GEJC regardless of prior treatments. Clinical trial information: NCT02500043. [Table: see text]

165 Background: The addition of intraperitoneal (IP) paclitaxel (PTX) to systemic chemotherapy comprising taxane/fluoropyrimidine doublet has shown promising results for patients with gastric cancer (GC) and peritoneal metastases (PM). However, this has not been studied in combination with platinum/fluoropyrimidine doublet which is the current standard-of-care for metastatic GC. We conducted a prospective phase 2 trial of IP PTX with capecitabine and oxaliplatin (XELOX) in patients with GCPM. Methods: The trial enrolled 44 patients with GCPM who received treatment comprising IP PTX (40mg/m2 on day 1,8), PO capecitabine (1000mg/m2 twice daily from day 1-14) and IV oxaliplatin (100mg/m2 on day 1) in 21-day cycles. Patients with synchronous GCPM were eligible for conversion surgery comprising radical gastrectomy if they had good response after chemotherapy, negative cytology on 2 consecutive peritoneal fluid assessments, no extraperitoneal metastasis and no peritoneal disease during surgery. The primary endpoint was overall survival and secondary endpoints were progression-free survival and safety. Outcomes from the trial were also compared with a retrospective cohort of 39 patients with GCPM who received identical systemic chemotherapy (SC) comprising platinum/fluoropyrimidine agents alone. Results: The median OS for the IP and SC groups was 14.6 and 10.6 months (HR 0.44; 95% CI, 0.26-0.74; P=0.002). The 1-year OS was 67.8% in the IP group and 32.3% in the SC group (Logrank p