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Background: Fluoropyrimidines are commonly used in the treatment of metastatic breast cancer (MBC), and trifluridine/tipiracil (FTD/TPI) has shown activity in patients with colorectal and gastric cancers despite prior exposure to fluoropyrimidines. We investigate the role of FTD/TPI in patients with MBC with or without prior fluoropyridines in a single-arm phase II study., Methods: Patients with MBC were enroled first into a run-in dose confirmation phase, followed by two parallel cohorts including patients with (Cohort A) and without (Cohort B) prior exposure to fluoropyrimidines, where they were treated with FTD/TPI. Primary objectives for each cohort included determination of progression-free survival (PFS), and secondary objectives included determination of objective response rates (ORR), safety, and tolerability., Results: Seventy-four patients (42 Cohort A, 32 Cohort B) were enroled, all of whom were evaluable for toxicity and survival, with 72 evaluable for response. Median PFS was 5.7 months (95% confidence interval 3.8-8.3) and 9.4 months (95% CI 5.5-14.0) respectively in Cohorts A and B. Responses were observed regardless of prior exposure to fluoropyrimidines, with ORR of 19.5% (95% CI 8.8-34.9) and 16.1% (95% CI 5.5-33.7) in Cohorts A and B, and 6-month clinical benefit rates of 56.1% (95% CI 39.7-71.5) and 61.3% (95% CI 42.2-78.2) respectively. The safety profile was consistent with known toxicities of FTD/TPI, including neutropenia, fatigue, nausea, and anorexia, mitigated with dose modifications., Conclusion: FTD/TPI showed promising antitumour activity with manageable toxicity and is a clinically valid option in patients with MBC., Competing Interests: Declaration of Competing Interest J SJ Lim: Honoraria and consulting – Astrazeneca, Roche, DKSH, MSD, Eisai, Novartis, Pfizer, Gilead Pharmaceuticals, Research funding – CTI Biopharma, Trael – AZD, Pfizer; A LA Wong: Honoraria and consulting – Astra Zeneca, Pfizer, Norvatis, Eisai, DKSH, Research funding – Otsuka Pharmaceuticals; S GW Ow: Honoraria and consulting – Astra Zeneca, Pfizer, Norvatis, Eli Lilly, Roche; R Sundar: Honoraria and consulting - Bristol-Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, GSK, DKSH, Astellas, Pierre-Fabre, Eili Lilly, BMS, Roche, Astra Zeneca, Ipsen; Research funding – Paxman Coolers, MSD, Natera; Patents – Paxman, Auristone; Travel – Roche, Astra Zeneca, Taiho, Eisai, DKSH. BC Tai: Honoraria and consulting – Boehringer Ingelheim, Royalty – Wiley-Blackwell; SC Lee: Honoraria and consulting – Astra Zeneca, Pfizer, Norvatis, Eli Lilly, Roche, ACT Genomics, Eisai, research funding – Taiho, Eisai, Pfizer, ACT Genomics. G HJ Chan, Y LE Ang, WQ Chong, M Lee, JL Low and J RE Choo, have no competing interests to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: The objective of this meta-analysis is to evaluate the impact of genetic polymorphisms on platinum-based chemotherapy (PBC)-induced ototoxicity., Data Sources: Systematic searches of PubMed, Embase, Cochrane, and Web of Science were conducted from the inception of the databases to May 31, 2022. Abstracts and presentations from conferences were also reviewed., Review Methods: Four investigators independently extracted data in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Differences in the prevalence of PBC-induced ototoxicity between reference and variant (i) genotypes and (ii) alleles were analyzed. The overall effect size was presented using the random-effects model as an odds ratio (OR) with a 95% confidence interval (CI)., Results: From 32 included articles, 59 single nucleotide polymorphisms on 28 genes were identified, with 4406 total unique participants. For allele frequency analysis, the A allele in ACYP2 rs1872328 was positively associated with ototoxicity (OR: 2.61; 95% CI: 1.06-6.43; n = 2518). Upon limiting to cisplatin use only, the T allele of COMT rs4646316 and COMT rs9332377 revealed significant results. For genotype frequency analysis, the CT/TT genotype in ERCC2 rs1799793 demonstrated an otoprotective effect (OR: 0.50; 95% CI: 0.27-0.94; n = 176). Excluding studies using carboplatin or concomitant radiotherapy revealed significant effects with COMT rs4646316, GSTP1 rs1965, and XPC rs2228001. Major sources of variations between studies include differences in patient demographics, ototoxicity grading systems, and treatment protocols., Conclusion: Our meta-analysis presents polymorphisms that exert ototoxic or otoprotective effects in patients undergoing PBC. Importantly, several of these alleles are observed at high frequencies globally, highlighting the potential for polygenic screening and cumulative risk evaluation for personalized care., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Background: Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, PD-L1-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented., Patients and Methods: KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1:1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary end point was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population., Results: Between May 5, 2016, and May 28, 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cutoff (November 30, 2020) was 45.1 months (interquartile range, 39.0-48.8). Median OS was 17.2 months (95% confidence interval [CI], 11.7-22.9) with pembrolizumab and 15.3 months (95% CI, 10.9-18.1) with chemotherapy (hazard ratio, 0.90 [95% CI, 0.67-1.19; P = 0.2262]). Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage)., Conclusion: Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events., Clinical Trial Registry: ClinicalTrials.gov, NCT02611960., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), and provides a target for a dendritic cell (DC) vaccine. CD137 ligand (CD137L) expressed on antigen presenting cells, costimulates CD137-expressing T cells, and reverse CD137L signaling differentiates monocytes to CD137L-DC, a type of DC, which is more potent than classical DC in stimulating T cells., Methods: In this phase I study, patients with locally recurrent or metastatic NPC were administered CD137L-DC pulsed with EBV antigens (CD137L-DC-EBV-VAX)., Results: Of the 12 patients treated, 9 received full 7 vaccine doses with a mean administered cell count of 23.9 × 10 6 per dose. Treatment was well tolerated with only 4 cases of grade 1 related adverse events. A partial response was obtained in 1 patient, and 4 patients are still benefitting from a progression free survival (PFS) of currently 2-3 years. The mean pre-treatment neutrophil: lymphocyte ratio was 3.4 and a value of less than 3 was associated with prolonged median PFS. Progressors were characterized by a high frequency of naïve T cells but a low frequency of CD8 + effector T cells while patients with a clinical benefit (CB) had a high frequency of memory T cells. Patients with CB had lower plasma EBV DNA levels, and a reduction after vaccination., Conclusion: CD137L-DC-EBV-VAX was well tolerated. The use of CD137L-DC-EBV-VAX is demonstrated to be safe. Consistent results were obtained from all 12 patients, indicating that CD137L-DC-EBV-VAX induces an anti-EBV and anti-NPC immune response, and warranting further studies in patients post effective chemotherapy., Precis: The first clinical testing of CD137L-DC, a new type of monocyte-derived DC, finds that CD137L-DC are safe, and that they can induce an immune response against Epstein-Barr virus-associated nasopharyngeal carcinoma that leads to tumor regression or prevents tumor progression., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer., Patients and Methods: Patients with advanced ER+/HER2- breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion., Results: Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0-11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%-42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%-68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%-40.7%), median DoR 6.9 months (IQR 5.9-13.1), and CBR 52.0% (95% CI, 31.3%-72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index., Conclusions: Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies., (©2022 American Association for Cancer Research.)

Background: Breast cancers are heterogeneous with variable clinical courses and treatment responses., Objective: We sought to evaluate dynamic changes in the molecular landscape of HER2-negative tumors treated with chemotherapy and anti-angiogenic agents., Patients and Methods: Newly diagnosed HER2-negative breast cancer patients received low-dose sunitinib or bevacizumab prior to four 2-weekly cycles of dose-dense doxorubicin and cyclophosphamide. Tumor biopsies were obtained at baseline, after 2 weeks and after 8 weeks of chemotherapy. Next-generation sequencing was performed to assess for single nucleotide variants (SNVs) and copy number alterations (CNAs) of 440 cancer-related genes (ACTOnco ® ). Observed genomic changes were correlated with the Miller-Payne histological response to treatment., Results: Thirty-four patients received sunitinib and 18 received bevacizumab. In total, 77% were hormone receptor positive (HER2-/HR+) and 23% were triple negative breast cancers (TNBC). New therapy-induced mutations were infrequent, occurring only in 13%, and appeared early after a single cycle of treatment. Seventy-two percent developed changes in the variant allele frequency (VAF) of pathogenic SNVs; the majority (51%) of these changes occurred early at 2 weeks and were sustained for 8 weeks. Changes in VAF of SNVs were most commonly seen in the PI3K/mTOR/AKT pathway; 13% developed changes in pathogenic mutations, which potentially confer sensitivity to PIK3CA inhibitors. Tumors with poor Miller-Payne response to treatment were less likely to experience changes in VAF of SNVs compared with those with good response (50% [7/14] vs 15% [4/24] had no changes observed at any timepoint, p = 0.029)., Conclusions: Serial molecular profiling identifies early therapy-induced genomic alterations, which may guide future selection of targeted therapies in breast cancer patients who progress after standard chemotherapy., Clinical Trial Registration: ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016)., (© 2022. The Author(s).)

The Beliefs about Medicines Questionnaire (BMQ) and Adherence Starts with Knowledge (ASK-12) questionnaire were originally developed and validated in Western populations to assess beliefs and barriers to medication adherence. The study aim is to validate the BMQ and ASK-12 questionnaire for use in a Singapore population with early stage breast cancer. English-speaking women on adjuvant endocrine therapy ( n  = 157) were recruited. The BMQ-Specific showed good internal consistency with structural validity. The internal consistency of BMQ-General and ASK-12 Behaviour scale improved with the new factor structure obtained from exploratory factor analysis. Further studies are needed to confirm these factor structures.

Purpose: Tumor angiogenesis controlled predominantly by vascular endothelial growth factor and its receptor (VEGF-VEGFR) interaction plays a key role in the growth and propagation of cancer cells. However, the newly formed network of blood vessels is disorganized and leaky. Pre-treatment with anti-angiogenic agents can "normalize" the tumor vasculature allowing effective intra-tumoral delivery of standard chemotherapy. Immunohistochemistry (IHC) analysis was applied to investigate and compare the vascular normalization and anti-angiogenic effects of two commonly used anti-angiogenic agents, Sunitinib and Bevacizumab, administered prior to chemotherapy in HER2-negative breast cancer patients., Methods: This prospective clinical trial enrolled 38 patients into a sunitinib cohort and 24 into a bevacizumab cohort. All received 4 cycles of doxorubicin/cyclophosphamide chemotherapy and pre-treatment with either sunitinib or bevacizumab. Tumor biopsies were obtained at baseline, after cycle 1 (C1) and cycle 4 (C4) of chemotherapy. IHC was performed to assess the tumor vascular normalization index (VNI), lymphatic vessel density (LVD), Ki67 proliferation index and expression of tumor VEGFR2., Results: In comparison to Bevacizumab, Sunitinib led to a significant increase in VNI post-C1 and C4 (p < 0.001 and 0.001) along with decrease in LVD post-C1 (p = 0.017). Both drugs when combined with chemotherapy resulted in significant decline in tumor proliferation after C1 and C4 (baseline vs post-C4 Ki67 index p = 0.006 for Sunitinib vs p = 0.021 for Bevacizumab). Bevacizumab resulted in a significant decrease in VEGFR2 expression post-C1 (p = 0.004)., Conclusion: Sunitinib, in comparison to Bevacizumab showed a greater effect on tumor vessel modulation and lymphangiogenesis suggesting that its administration prior to chemotherapy might result in improved drug delivery., Trial Registry: ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016)., (© 2021. The Author(s).)

Nasopharyngeal cancer (NPC), a cancer derived from epithelial cells in the nasopharynx, is a cancer common in China, Southeast Asia, and Africa. The three-dimensional (3D) genome organization of nasopharyngeal cancer is poorly understood. A major challenge in understanding the 3D genome organization of cancer samples is the lack of a method for the characterization of chromatin interactions in solid cancer needle biopsy samples. Here, we developed Biop-C, a modified in situ Hi-C method using solid cancer needle biopsy samples. We applied Biop-C to characterize three nasopharyngeal cancer solid cancer needle biopsy patient samples. We identified topologically associated domains (TADs), chromatin interaction loops, and frequently interacting regions (FIREs) at key oncogenes in nasopharyngeal cancer from the Biop-C heatmaps. We observed that the genomic features are shared at some important oncogenes, but the patients also display extensive heterogeneity at certain genomic loci. On analyzing the super enhancer landscape in nasopharyngeal cancer cell lines, we found that the super enhancers are associated with FIREs and can be linked to distal genes via chromatin loops in NPC. Taken together, our results demonstrate the utility of our Biop-C method in investigating 3D genome organization in solid cancers., Competing Interests: MF declares two patents on methodologies related to ChIA-PET. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Animesh, Choudhary, Wong, Koh, Ng, Tay, Chong, Jian, Chen, Goh and Fullwood.)

Purpose: To identify a structure to explain the relationship between socio-clinico factors, necessity-concerns beliefs, and perceived barriers to adherence with adjuvant endocrine therapy (AET) amongst women with breast cancer., Methods: Participants were 244 patients with early-stage breast cancer recruited from two tertiary hospitals from May 2015 to December 2018 who completed questionnaires on medication adherence (Simplified Medication Adherence Questionnaire), necessity-concerns beliefs (Beliefs about Medicine Questionnaire), and barriers to adherence (Adherence Starts with Knowledge Questionnaire). Socio-clinico variables were collected via interview and medical records review. Structural equation modelling was applied to examine the relationships between these variables and possible mediating effects of necessity-concerns beliefs on adherence to AET., Results: The median age of the study participants was 61 (range 32-80) years and the median duration on AET was 1.6 (IQR 1.2-2.6) years. Adherence was positively associated with age (β = 0.145, 95% CI: 0.011 to 0.279, p = 0.034) and negatively associated with barriers (β = - 0.381, 95% CI: - 0.511 to - 0.251, p < 0.001). There was no effect of Necessity (β = 0.006, 95% CI: - 0.145 to 0.158, p = 0.933) or Concerns (β = 0.041, 95% CI: - 0.117 to 0.199, p = 0.614) on adherence. Necessity-concerns beliefs were also not significant mediators in the relationship between socio-clinico factors and medication adherence., Conclusions: Older age and lower barriers to adherence were associated with higher adherence scores. Necessity-concerns beliefs did not have a significant effect on adherence as majority of the patients identified forgetfulness as a reason for non-adherence., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Complementary and alternative medicine (CAM) is often used by cancer patients and is concerning as concomitant oral CAM and chemotherapy use may result in adverse interactions and toxicities. We hypothesise that a decision aid (DA) may promote informed and rational use of oral CAM during chemotherapy, and increase patients' discussion with their oncologists on CAM use., Methods: We randomised 240 patients initiating chemotherapy to receive DA or none. Questionnaires were administered at randomisation (visit 1), 1 month (visit 2) and 3 months (visit 3). The primary endpoint was the decisional conflict score (DCS) for decision made on CAM use during chemotherapy. Secondary endpoints include patients' decision regret score (DRS) on CAM use, CAM uptake, discussion with oncologists on CAM usage, and difference in quality of life (QoL) score between CAM and non-CAM users at visit 3., Results: There was no difference in the mean DCS (mean difference 2.7 [95 CI - 2.9 to 8.3, p = 0.345]) and DRS (mean difference - 0.3 [95% CI - 6.3 to 5.8, p = 0.926]) between the two arms. There was a reduction in odds of CAM usage in the intervention arm compared to control arm (OR = 0.36, 95% CI 0.17 to 0.78, p = 0.009), but there was no difference in discussion with oncologists on CAM usage (OR = 0.46, 95% CI 0.07 to 3.01, p = 0.419), or in the QoL between CAM and non-CAM users., Conclusion: Our DA did not reduce DCS among cancer patients on chemotherapy. DA that provides more evidence-based information on CAM, and non-judgemental discussion initiated by oncologists to discuss CAM, may improve its effectiveness.

Background: The approved doses of the single agent nivolumab - an anti-programmed cell death protein 1 (PD-1) monoclonal antibody - for renal cell carcinoma (RCC) are 3 mg/kg and a 240-mg flat dose, despite efficacy shown at lower doses in earlier CheckMate trials. In view of financial constraints, the minimum dose of nivolumab required for efficacy remains a critical area of inquiry., Methods: A retrospective review of RCC patients receiving single-agent anti-PD-1 treatment was conducted. Using the median cutoff of the maximum dose per body weight received, we investigated the effect of lower dosages on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and immune-related adverse event-free survival (irAE-FS). Survival analysis was made by Kaplan-Meier, by uni- and multivariable Cox models, and by modeling the statistical interaction between dosages and survival., Results: 32 patients were recruited: 8 patients (25%) receiving first-line treatment and 24 (75%) receiving second-line treatment and beyond. A median split at 2.15 mg/kg yielded 16 patients in both the lower-dose (LD) and the higher-dose (HD) cohort. Hazard ratios (HRs) demonstrated no difference in OS after adjustment for gender (HR = 0.22, 95% CI 0.05-1.05, p = 0.054; favoring LD), as well as in PFS after adjustment for gender and concurrent radiation therapy (HR = 0.58, 95% CI 0.25-1.34, p = 0.210; favoring LD). No differences in ORR were observed (50.0 vs. 43.8%, p = 1.00, in the LD and the HD cohort, respectively). Immune-related phenomena were observed in the LD group, including pseudoprogression and increased all-grade immune-related toxicities (irAE-FS: HR = 1.72, 95% CI 0.48-6.14, p = 0.293; favoring HD). Iterative dichotomization of dosages showed no dose-OS or dose-irAE-FS relationship., Conclusion: Our study suggests no apparent reduction in efficacy when using a low-dosage nivolumab regimen., (© 2021 S. Karger AG, Basel.)

Background: We 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., Methods: Patients with advanced solid cancers were randomized 1:1 to 3-weekly docetaxel 75 mg/m 2 , 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)., Results: We 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)., Conclusions: The 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 Registration: The study was registered ( NCT01803503 ) prospectively on clinicaltrials.gov on 4th March 2013.

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 18 FDG 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., (©2020 American Association for Cancer Research.)

Background: Medication adherence is crucial for improving clinical outcomes in the treatment of patients. We evaluate the effect of short message service (SMS) reminder on medication adherence and serum hormones in patients with breast cancer on aromatase inhibitors., Methods: An open-label, multi-centre, prospective randomised controlled trial of SMS versus Standard Care was conducted. Medication adherence was assessed via self-report using the Simplified Medication Adherence Questionnaire at baseline, 6 month, and 1 year. Androstenedione, estradiol, and estrone were measured at baseline and 1 year. The χ 2 test and mixed effects logistic regression was performed to compare medication adherence between groups. Difference in androstenedione and estrone levels were assessed using analysis of covariance, whereas χ 2 test and logistic regression was used for estradiol. Analysis was based on intention-to-treat., Results: A total of 244 patients were randomised to receive weekly SMS reminder (n = 123) or Standard Care (n = 121) between May 2015 and December 2018. The odds of adherence was higher at 6-month in SMS (OR = 1.78, 95% CI 1.04-3.05, p = 0.034), and not significantly different at 1-year (OR = 1.15, 95% CI: 0.67-1.96 p = 0.617). Mixed effects logistic regression analysis showed higher odds of adherence in SMS over the 1-year period (OR = 2.35, 95% CI: 1.01-5.49, p = 0.048). There was no difference in serum hormone levels between groups., Conclusion: SMS reminder improved medication adherence in the short-term but had no effect on serum hormones levels in the longer term. Future studies could investigate the use of tailored SMS intervention according to patient preference to improve its sustainability., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest that is related to this submission., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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 × 10 7 /kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 10 7 /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., (©2020 American Association for Cancer Research.)

Background: The importance of immune-checkpoint inhibitors (ICI) can no longer be understated since its move to front-line treatment in non-small cell lung cancer (NSCLC) in recent years. However, the safety and efficacy of ICI in special populations such as those with infections like tuberculosis (TB) and hepatitis B (HBV) remain unknown as they are routinely excluded from clinical trials., Methods: Records of patients with advanced NSCLC who were treated with ICI from January 2014 to June 2019 at a single Asian centre were reviewed. Those with a history of HBV and/or TB were selected. In this group, safety and treatment outcomes including overall survival (OS), progression-free survival (PFS) and response rate were reported and compared against control., Results: 191 patients received ICI, 47 (24.6%) had a history of TB/HBV. The median PFS in those with a history of TB/HBV was 5.7 months (95% CI 3.9-7.6), compared to 3.1 months (95% CI 2.4-3.8) in control (HR 0.61, 95% CI 0.39-0.93, p = 0.021). Median OS was 15.6 months (95% CI 10.2-21.0) compared to 11.1 months (95% CI 7.6-14.7 months) in the control group (HR 0.58, 95% CI 0.34-0.99, p = 0.046). Adverse events of any grade (G) were similar in both groups; slightly more patients with TB/HBV experienced G3 or higher adverse events. Four patients developed TB after initiation of ICI, none with previously documented TB experienced reactivation. Of the 42 patients with a history of HBV, eight had inactive chronic HBV and six had detectable viral load. None of the 34 patients who were previously exposed to HBV had reactivation., Conclusion: The use of ICI appears to be safe and efficacious in patients with TB/HBV infection. Prospective studies are required to identify those at risk in order to optimise care to these groups of patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)