ENABLE-SG (Educate, Nurture, Advise, Before Life Ends for Singapore) as a proactive palliative care model: protocol for a hybrid type 1 effectiveness-implementation randomized wait-list controlled trial.

BACKGROUND: Specialist palliative care is often provided late in the patient's disease trajectory in response to uncontrolled symptoms. Shifting from this reactionary illness-stress paradigm to a proactive health-wellness approach, the ENABLE (Educate, Nurture, Advise, Before Life Ends) telehealth model aims to enhance the coping, stress and symptom management, self-care, and advance care planning skills of patients with advanced cancers and their caregivers. The ENABLE model has been culturally adapted to Singapore (ENABLE-SG) and pilot-tested. A hybrid type 1 effectiveness-implementation design will be used to evaluate the effectiveness of ENABLE-SG while collecting real-world implementation data. METHODS: This single-centre, assessor-blind, wait-list (immediately vs. 6 months) randomized controlled trial will recruit 300 adult patients within 60 days of an advanced cancer diagnosis and their family caregivers from the National Cancer Centre of Singapore. ENABLE-SG comprises structured psychoeducational sessions with a telehealth coach, covering essential topics of early palliative care. Participants will be assessed at baseline and every 3 months until patient's death, 12 months (caregivers), or end of study (patients). The primary outcome is patient quality of life 6 months after baseline. Secondary patient-reported outcomes include mood, coping, palliative care concerns, and health status. Secondary caregiver-reported outcomes include caregiver quality of life, mood, coping, and care satisfaction. Mixed-effects regression modelling for repeated measurements will be used. To assess the effectiveness of ENABLE-SG versus usual care, patient and caregiver outcomes at 6 months will be compared. To compare earlier versus delayed ENABLE-SG, patient and caregiver outcomes at 12 months will be compared. Within the hybrid type 1 effectiveness-implementation design, implementation outcomes will be evaluated in both the early and delayed groups. Acceptability, adoption, appropriateness, and feasibility will be assessed using a feedback survey and semi-structured interviews with a purposive sample of patients, caregivers, and healthcare providers. Transcribed interviews will be analysed thematically. Other implementation outcomes of penetration, fidelity, and cost will be assessed using records of study-related processes and summarized using descriptive statistics. A cost-effectiveness analysis will also be conducted. DISCUSSION: This study will assess both effectiveness and implementation of ENABLE-SG. Insights into implementation processes can facilitate model expansion and upscaling. TRIAL REGISTRATION: Registered prospectively on ClinicalTrials.gov, NCT06044441. Registered on 21/09/2023.

Early Triple-Negative Breast Cancers in a Singapore Cohort Exhibit High PIK3CA Mutation Rates Associated With Low PD-L1 Expression.

Mutations in the PI3K pathway, particularly PIK3CA, were reported to be intimately associated with triple-negative breast cancer (TNBC) progression and the development of treatment resistance. We profiled PIK3CA and other genes on 166 early-stage TNBC tumors from Singapore for comparison to publicly available TNBC cohorts. These tumors were profiled transcriptionally using a NanoString panel of immune genes and multiplex immunohistochemistry, then manually scored for PD-L1-positivity using 2 clinically relevant clones, SP142 and 22C3. We discovered a higher rate of PIK3CA mutations in our TNBC cohort than in non-Asian cohorts, along with TP53, BRCA1, PTPN11, and MAP3K1 alterations. PIK3CA mutations did not affect overall or recurrence-free survival, and when compared with PIK3CAWT tumors, there were no differences in immune infiltration. Using 2 clinically approved antibodies, PIK3CAmut tumors were associated with PD-L1 negativity. Analysis of comutation frequencies further revealed that PIK3CA mutations tended to be accompanied by MAP kinase pathway mutation. The mechanism and impact of PIK3CA alterations on the TNBC tumor immune microenvironment and PD-L1 positivity warrant further study.

Multi-center evaluation of artificial intelligent imaging and clinical models for predicting neoadjuvant chemotherapy response in breast cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) plays an important role in the management of locally advanced breast cancer. It allows for downstaging of tumors, potentially allowing for breast conservation. NAC also allows for in-vivo testing of the tumors' response to chemotherapy and provides important prognostic information. There are currently no clearly defined clinical models that incorporate imaging with clinical data to predict response to NAC. Thus, the aim of this work is to develop a predictive AI model based on routine CT imaging and clinical parameters to predict response to NAC. METHODS: The CT scans of 324 patients with NAC from multiple centers in Singapore were used in this study. Four different radiomics models were built for predicting pathological complete response (pCR): first two were based on textural features extracted from peri-tumoral and tumoral regions, the third model based on novel space-resolved radiomics which extract feature maps using voxel-based radiomics and the fourth model based on deep learning (DL). Clinical parameters were included to build a final prognostic model. RESULTS: The best performing models were based on space-resolved and DL approaches. Space-resolved radiomics improves the clinical AUCs of pCR prediction from 0.743 (0.650 to 0.831) to 0.775 (0.685 to 0.860) and our DL model improved it from 0.743 (0.650 to 0.831) to 0.772 (0.685 to 0.853). The tumoral radiomics model performs the worst with no improvement of the AUC from the clinical model. The peri-tumoral combined model gives moderate performance with an AUC of 0.765 (0.671 to 0.855). CONCLUSIONS: Radiomics features extracted from diagnostic CT augment the predictive ability of pCR when combined with clinical features. The novel space-resolved radiomics and DL radiomics approaches outperformed conventional radiomics techniques.

Integrating immunotherapy in the (neo)adjuvant setting of early breast cancer.

PURPOSE OF REVIEW: Breast cancer is a relative latecomer in the success story of immuno-oncology. In this review, we focus on the preclinical and clinical lines of evidence to justify the evaluation of immune checkpoint inhibition (ICI) for the curative-intent treatment of breast cancer, the latest and ongoing trials of (neo)adjuvant immunotherapy, and practical considerations in clinical practice associated with this new treatment paradigm. RECENT FINDINGS: Insights from the immunobiology of breast cancer have paved the way for the new frontier of immunotherapy in this malignancy, starting from advanced stages and moving onto curable cases. Tumor-infiltrating lymphocyte quantification and PD-L1 immunohistochemistry are forerunners of predictive biomarkers for sensitivity to ICI in breast cancers. Preliminary results from phase III trials of combinatorial immunochemotherapy to treat early high-risk or locally advanced triple-negative breast cancer are encouraging for pathological complete response. Additional efficacy and patient-reported outcomes of (neo)adjuvant immunochemotherapy trials are awaited. SUMMARY: The prospect of integrating ICI in the treatment of early-stage breast cancer is promising. Questions regarding patient selection, the choice of ICI agent and combination partner in escalation strategies, sequencing and duration of treatments, cost-effectiveness and mechanisms of resistance remain to be answered by future research.

Referrals to a Phase I Clinic and Trial Enrollment in the Molecular Screening Era.

BACKGROUND: Enrichment of patients based on molecular biomarkers is increasingly used in early phase clinical trials. Molecular profiling of patients with advanced cancers can identify specific genomic alterations to inform decisions about investigational treatment(s). Our aim was to evaluate the outcomes of new patient referrals to a large academic solid tumor phase I clinical trial program after the implementation of molecular profiling. MATERIALS AND METHODS: Retrospective chart review of all new referrals to the Princess Margaret Cancer Centre (PM) phase I clinic from May 2012 to December 2014. Molecular profiling using either MALDI-TOF hotspot mutation genotyping or targeted panel DNA sequencing was performed for patients at PM or community hospitals through the institutional IMPACT/COMPACT trials. RESULTS: A total of 971 new patient referrals were included for this analysis. Twenty-seven percent of referrals assessed in clinic were subsequently enrolled in phase I trials. Of all new referrals, 41% had prior molecular profiling, of whom 11% (n = 42) were enrolled in genotype-matched trials. Patients with prior molecular profiling were younger, more heavily pretreated, and had more favorable Princess Margaret Hospital Index (PMHI) scores. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (p = .002), internal referrals within PM (p = .002), and PMHI (p ≤ .001) were independently associated with successful trial enrollment in multivariable analysis. CONCLUSION: Although nearly half of new patients referred to a phase I clinic had prior molecular profiling, the proportion subsequently enrolled into clinical trials was low. Prior molecular profiling was not an independent predictor of clinical trial enrollment. IMPLICATIONS FOR PRACTICE: The landscape of oncology drug development is evolving alongside technological advancements. Recently, large academic medical centers have implemented clinical sequencing protocols to identify patients with actionable genomic alterations to enroll in therapeutic clinical trials. This study evaluates patient referral and enrollment patterns in a large academic phase I clinical trials program following the implementation of a molecular profiling program. Performance status and referral from a physician within the institution were associated with successful trial enrollment, whereas prior molecular profiling was not an independent predictor.

Association of mitochondrial DNA content in peripheral blood with cancer-related fatigue and chemotherapy-related cognitive impairment in early-stage breast cancer patients: a prospective cohort study.

PURPOSE: Cancer-related fatigue (CRF) and chemotherapy-related cognitive impairment (CRCI) are reported to be associated with mitochondrial dysfunction. Hence, mitochondrial DNA (mtDNA) content, a biomarker of mitochondrial dysfunction, is hypothesized to correlate with the onset of CRF and CRCI. This study aims to evaluate the association between peripheral blood mtDNA content reduction and severity of CRF and CRCI in patients receiving chemotherapy. METHODS: This was a prospective cohort study. Early-stage breast cancer patients receiving anthracycline- or taxane-based chemotherapy were recruited. CRF was assessed using MFSI-SF, and CRCI was assessed using FACT-Cog and CANTAB at two timepoints: baseline (T1; prior to treatment) and 6 weeks after initiation of treatment (T2). mtDNA content was measured at both timepoints using real-time quantitative polymerase chain reaction. Multiple logistic regression was utilized to evaluate the association between mtDNA reduction and worsening of CRF and CRCI, adjusting for age, anxiety, insomnia, plasma cytokines concentrations, and other clinically important covariates. RESULTS: A total of 108 patients (age 52.0 ± 9.2 years; 82.4% Chinese; 64.8% receiving anthracycline-based chemotherapy) were recruited. Proportions of patients with worsening of CRF increased from the lower to the upper quartiles of mtDNA reduction (22.2, 33.3, 55.6, and 63.0% in quartiles 1, 2, 3, and 4, respectively, p = 0.001 for trend). Reduction of mtDNA content was significantly greater among those with worsening of CRF and CRCI compared to those without CRF [mean reduction (± SD): 36.5 (46.1) vs. 9.4 (34.5), p < 0.001]. After adjusting for covariates, every 1-unit reduction of the mtDNA content was associated with a 4% increased risk for worsening of CRF (95% CI, 1-6%; p = 0.009). CONCLUSIONS: This is the first study to show that the reduction of mtDNA content in peripheral blood is associated with the onset of CRF in patients receiving chemotherapy. Further validation studies are required to confirm the findings.

Curative Approaches for Metaplastic Breast Cancer: A Retrospective Cohort Outcome Review.

PURPOSE: Metaplastic breast cancer (MBC) is a rare and heterogeneous breast cancer subtype, and there are critical gaps in our understanding of its long-term outcomes. This retrospective cohort study aimed to address these gaps by scrutinizing the pathologic and clinical aspects of MBC to enhance clinical decision-making and refine patient care strategies. METHODS AND MATERIALS: This registry-based retrospective cohort study included women aged ≥21 years diagnosed with MBC or matrix-producing carcinoma. The data were obtained from January 2001 to August 2020 from the Joint Breast Cancer Registry of Singapore Health Services, which included 23,935 patients. Demographic and clinicopathologic characteristics, neoadjuvant chemotherapy responses, and survival outcomes were analyzed. Statistical assessments involved univariate and multivariate Cox proportional hazards models and Kaplan-Meier survival analyses. RESULTS: This study enrolled 170 patients; 87.1% had non-metastatic disease, and 12.9% had metastatic disease. The age of patients at diagnosis ranged from 46 to 65 years (median, 56 years). The cohort's predominant characteristics were triple negative breast cancer (64%), advanced clinical stage (77.6%), node negativity (67.6%), and grade 3 disease (74.1%). In patients receiving neoadjuvant chemotherapy with curative intent treatment (17.6%), neoadjuvant chemotherapy yielded a pathologic complete response of 19.2% and a disease progression rate of 46.2%. Multivariate analysis showed that adjuvant radiation therapy significantly improved overall survival and disease-free survival, with hazard ratios of 0.29 (95% CI, 0.13-0.62; P < .005) and 0.23 (95% CI, 0.10-0.50; P < .005), respectively. Clinical T3 and T4 stages and nodal involvement were associated with poor outcomes. Stable disease after neoadjuvant chemotherapy was associated with poor overall survival and disease-free survival. CONCLUSIONS: This study sheds light on the complex landscape of MBC and emphasizes the pivotal role of adjuvant radiation therapy in enhancing patient outcomes. Despite advancements, challenges persist that warrant continued research to refine neoadjuvant chemotherapy strategies and delve into the nuanced factors that influence treatment responses.

Phase II DORA Study of Olaparib with or without Durvalumab as a Chemotherapy-Free Maintenance Strategy in Platinum-Pretreated Advanced Triple-Negative Breast Cancer.

PURPOSE: We explored the efficacy of PARP inhibition with or without programmed death ligand-1 (PD-L1) blockade as chemotherapy-free maintenance therapy for advanced triple-negative breast cancer (aTNBC) sensitive to platinum-based chemotherapy. PATIENTS AND METHODS: In the phase II non-comparative DORA trial (NCT03167619), patients with ongoing stable disease (SD) or complete/partial response (CR/PR) to first- or second-line platinum-based chemotherapy for TNBC (≤10% estrogen/progesterone receptor expression) were randomized 1:1 to receive olaparib 300 mg twice daily with or without durvalumab 1,500 mg on day 1 every 4 weeks. The primary objective was to compare progression-free survival (PFS) versus a historical control of continued platinum-based therapy. RESULTS: 45 patients were randomized (23 to olaparib alone, 22 to the combination; 3 with estrogen/progesterone receptor expression 1%-10%). At 9.8 months' median follow-up, median PFS from randomization was 4.0 [95% confidence interval (CI), 2.6-6.1] months with olaparib and 6.1 (95% CI, 3.7-10.1) months with the combination, both significantly longer than the historical control (P = 0.0023 and P < 0.0001, respectively). Clinical benefit rates (SD ≥24 weeks or CR/PR) were 44% (95% CI, 23%-66%) and 36% (95% CI, 17%-59%) in the monotherapy and combination arms, respectively. Sustained clinical benefit was seen irrespective of germline BRCA mutation or PD-L1 status, but tended to be associated with CR/PR to prior platinum, particularly in the olaparib-alone arm. No new safety signals were reported. CONCLUSIONS: PFS was longer than expected with both regimens. A patient subset with wild-type BRCA platinum-sensitive aTNBC had durable disease control with chemotherapy-free maintenance.

The cardioprotective potential of sodium-glucose cotransporter 2-inhibitors in breast cancer therapy-related cardiac dysfunction - A systematic review.

BACKGROUND: Sodium-glucose cotransporter 2-inhibitors (SGLT2i) improve cardiovascular outcomes including reduction in risk of first hospitalisation for heart failure (HF), worsening HF and cardiovascular death regardless of HF or diabetes mellitus (DM) status. It is not known whether SGLT2i can prevent the development of incident HF or reduce the risk of HF in patients receiving trastuzumab with or without other concurrent anti-HER2 agent or sequential anthracycline for treatment of HER2 positive breast cancer. Patients with active malignancy or recent history of malignancy were excluded from participating in the main cardiovascular outcome trials involving SGLT2i. AIM: A systematic review was performed to objectively assess published literature on the cardioprotective effects of SGLT2i in breast cancer treatment-related cardiotoxicity. METHODS: Systematic searches of Embase, Medline, The Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases were performed. Titles and abstracts were screened separately by two cardio-oncologists (JHC, WTC). Full texts of potentially eligible records were then assessed separately by JHC and WTC before inclusion into review upon joint agreement. RESULTS: 479 records were identified from 3 databases (MEDLINE=51, EMBASE=408, CENTRAL=13) and 1 registry (Clinicaltrials.gov=7). 460 records were excluded based on title and abstract (including duplicates). 19 full text reports were assessed for eligibility and included in review (basic science/animal study paper 2, Clinicaltrials.gov randomised controlled trial submission 1 (currently recruiting), basic science/animal study conference abstract 5, case report 2, review 3, editorial comment 2, clinical guidelines 1, retrospective/registry-based conference abstract 3). CONCLUSION: Cardiotoxicity is the most common dose-limiting toxicity associated with trastuzumab. Discontinuation of trastuzumab however, can lead to worse cancer outcomes. There have been case reports, registry-based, retrospective cohort-based and mechanistic studies suggesting the cardioprotective potential of SGLT2i in cancer therapy-related cardiac dysfunction (CTRCD). Based on these, there is now a call for randomised controlled trials to be performed in this patient cohort to advise guideline-directed therapy for CTRCD, which will in turn also provide detailed safety information and improve cancer and cardiovascular outcomes.

External validation of the first prognostic nomogram for older adults with cancer.

Background: The geriatric oncology population tends to be complex because of multimorbidity, functional and cognitive decline, malnutrition and social frailty. Prognostic indices for predicting survival of elderly cancer patients to guide treatment remain scarce. A nomogram based on all domains of the geriatric assessment was previously developed at the National Cancer Centre Singapore (NCCS) to predict overall survival (OS) in elderly cancer patients. This nomogram comprised of six variables (age, eastern cooperative oncology group performance status, disease stage, geriatric depression scale (GDS), DETERMINE nutritional index and serum albumin). Objectives: To externally validate the NCCS prognostic nomogram. Design: This is a prospective cohort study. Methods: The nomogram was developed based on a training cohort of 249 patients aged ⩾70 years who attended the NCCS outpatient geriatric oncology clinic between May 2007 and November 2010. External validation of the nomogram using the Royston and Altman approach was carried out on an independent testing cohort of 252 patients from the same clinic between July 2015 and June 2017. Model misspecification, discrimination and calibration were assessed. Results: Median OS of the testing cohort was 3.1 years, which was significantly higher than the corresponding 1.0 year for the training cohort (log-rank p < 0.001). The nomogram achieved a high level of discrimination in the testing cohort (0.7112), comparable to the training cohort (0.7108). Predicted death probabilities were generally well calibrated with the observed death probabilities, as the joint test of calibration-in-the-large estimates at year 1, 2 and 3 from zeros and calibration slope from one was insignificant with p = 0.432. There were model misspecifications in GDS and serum albumin. Conclusion: This study externally validated the prognostic nomogram in an independent cohort of geriatric oncology patients. This supports the use of this nomogram in clinical practice.

The impact of irritable bowel syndrome on health-related quality of life: a Singapore perspective.

BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. The prevalence of IBS in Asian countries varies from 2.9% to 15.6%. IBS does not result in increased mortality, but is associated with psychological distress and disruption of work and sleep. Consequently, the evaluation of health-related quality of life (HRQoL) is an important outcome measure for patients with IBS since it provides a holistic assessment of the patient's emotional, social and physical function. However, some HRQoL tools can be time-consuming to apply. EQ-5D is a brief HRQoL tool which has been validated in the Western IBS population but has thus far not been used in Asia. This study was conducted to determine whether persons with self-reported symptoms that met the Rome III criteria for IBS had a poorer quality of life than those without these symptoms. We also aimed to determine which specific aspects of quality of life were most affected and whether any risk factors distinguished those with and without IBS. METHODS: Self-administered questionnaires which included the Rome III diagnostic questionnaire modules for IBS and the EQ-5D questionnaire were obtained from participants of a health symposium in Singapore on 31th October 2010. IBS was diagnosed based on the Rome III Criteria. The main outcome measure was the EQ-5D index score. The relationship between the presence of IBS and the EQ-5D index score, individual dimensions of EQ-5D and demographic risk factors were examined. RESULTS: 449 completed questionnaires were analyzed. The mean EQ-5D index score for IBS was 0.739 which was a significant reduction compared to non-IBS participants [-0.11 (95% CI: -0.15 to -0.07), p<0.001]. Multivariate analysis showed that IBS was significantly associated with younger age and higher education level. Of the five EQ-5D dimensions, IBS sufferers were significantly affected in mobility, anxiety or depression, usual activity and pain. There was a "dose related" increase in likelihood of having IBS with increased severity of pain and anxiety or depression. CONCLUSION: IBS sufferers have significantly poorer quality of life. Assessment of HRQoL in IBS using the EQ-5D should be considered in further studies and routine clinical practice.

Clinical best practices in optimal monitoring, early diagnosis, and effective management of antibody-drug conjugate-induced interstitial lung disease or pneumonitis: a multidisciplinary team approach in Singapore.

INTRODUCTION: Interstitial lung disease (ILD) or pneumonitis remains an important adverse event identified with treatment with antibody-drug conjugates (ADCs). Drug-induced ILD (DILD) accounts for 3%-5% of common ILD cases and is a significant problem in clinical practice. Hence, with the anticipation of the widespread use of ADCs, it will be important for guidelines and recommendations to be established to direct and standardize the management of DILD by a multidisciplinary team (MDT). AREAS COVERED: A thorough literature search was conducted using PubMed to identify relevant articles related to ADCs published between 1 January 2010 and 31 November 2022. Based on the review of the literature combined with expert opinions, this review article offers an overview of incidences of ILDs associated with the use of newer anticancer therapies, specifically ADCs, and discusses local-regional best practices in optimal monitoring, early diagnosis, and management of DILD involving an MDT. EXPERT OPINION: Multidisciplinary input and consensus are crucial in the accurate diagnosis of DILD. The core group of essential attendees in the MDT are oncologists, pulmonologists, thoracic radiologists, and pathologists. This allows for the integration of expertise from different specialists to achieve a 'best fit' diagnosis and management.

A phase 1 study of the safety, pharmacokinetics and pharmacodynamics of escalating doses followed by dose expansion of the selective inhibitor of nuclear export (SINE) selinexor in Asian patients with advanced or metastatic malignancies.

Purpose: This phase 1 study aims to evaluate the tolerability and the recommended phase 2 dose of selinexor in Asian patients with advanced or metastatic malignancies. Experimental Design: A total of 105 patients with advanced malignancies were enrolled from two sites in Singapore (National University Hospital and the National Cancer Centre, Singapore) from 24 February 2014 to 14 January 2019. We investigated four dosing schedules of selinexor in a 3 + 3 dose escalation design with an additional Phase 1b expansion cohort. Adverse events were graded with the NCI Common Terminology Criteria for Adverse Events v 4.03. Pharmacodynamic assessments included nuclear cytoplasmic localization of p27, XPO1 cargo proteins pre and post selinexor dosing and pharmacokinetic assessments were conducted at doses between 40 and 60 mg/m2. Results: In our Asian patient cohort, dosing at 40 mg/m2 given 2 out of 3 weeks, was the most tolerable for our patients. At this dose level, grade 3 adverse events included fatigue (8%), hyponatremia (23%), vomiting (5%), thrombocytopenia (5%), and anaemia (2%). Selinexor had a rapid oral absorption with median Tmax of 2 h and no PK accumulation after multiple doses of tested regimens. Complete responses were seen in two lymphoma patients. Partial responses were noted in three diffuse large B cell lymphomas, one Hodgkin's lymphoma and thymic carcinoma patient, respectively. Conclusion: Selinexor is tolerated by Asian patients at 40 mg/m2 twice a week given 2 out of 3 weeks. A 1-week drug holiday was needed as our patients could not tolerate the current approved continuous dosing regimens because of persistent grade 3 fatigue, anorexia and hyponatremia.

Association between Breast Cancer Polygenic Risk Score and Chemotherapy-Induced Febrile Neutropenia: Null Results.

BACKGROUND: The hypothesis that breast cancer (BC) susceptibility variants are linked to chemotherapy-induced toxicity has been previously explored. Here, we investigated the association between a validated 313-marker-based BC polygenic risk score (PRS) and chemotherapy-induced neutropenia without fever and febrile neutropenia (FNc) in Asian BC patients. METHODS: This observational case-control study of Asian BC patients treated with chemotherapy included 161 FNc patients, 219 neutropenia patients, and 936 patients who did not develop neutropenia. A continuous PRS was calculated by summing weighted risk alleles associated with overall, estrogen receptor- (ER-) positive, and ER-negative BC risk. PRS distributions neutropenia or FNc cases were compared to controls who did not develop neutropenia using two-sample t-tests. Odds ratios (OR) and corresponding 95% confidence intervals were estimated for the associations between PRS (quartiles and per standard deviation (SD) increase) and neutropenia-related outcomes compared to controls. RESULTS: PRS distributions were not significantly different in any of the comparisons. Higher PRSoverall quartiles were negatively correlated with neutropenia or FNc. However, the associations were not statistically significant (PRS per SD increase OR neutropenia: 0.91 [0.79-1.06]; FNc: 0.87 [0.73-1.03]). No dose-dependent trend was observed for the ER-positive weighted PRS (PRSER-pos) and ER-negative weighted PRS (PRSER-neg). CONCLUSION: BC PRS was not strongly associated with chemotherapy-induced neutropenia or FNc.

A phase I study of an adenoviral vector delivering a MUC1/CD40-ligand fusion protein in patients with advanced adenocarcinoma.

Cancer vaccines as immunotherapy for solid tumours are currently in development with promising results. We report a phase 1 study of Ad-sig-hMUC1/ecdCD40L (NCT02140996), an adenoviral-vector vaccine encoding the tumour-associated antigen MUC1 linked to CD40 ligand, in patients with advanced adenocarcinoma. The primary objective of this study is safety and tolerability. We also study the immunome in vaccinated patients as a secondary outcome. This trial, while not designed to determine clinical efficacy, reports an exploratory endpoint of overall response rate. The study meets its pre-specified primary endpoint demonstrating safety and tolerability in a cohort of 21 patients with advanced adenocarcinomas (breast, lung and ovary). The maximal dose of the vaccine is 1 ×1011 viral particles, with no dose limiting toxicities. All drug related adverse events are of low grades, most commonly injection site reactions in 15 (71%) patients. Using exploratory high-dimensional analyses, we find both quantitative and relational changes in the cancer immunome after vaccination. Our data highlights the utility of high-dimensional analyses in understanding and predicting effective immunotherapy, underscoring the importance of immune competency in cancer prognosis.

Candida Endophthalmitis Treated Successfully With Isavuconazole: A Case Report.

Candida endophthalmitis is a serious complication of candidemia. Diagnosis requires identification of ocular lesions on dilated fundoscopy, aided by isolation of the organism from blood and/or vitreous humor. However, the initial ophthalmological examination may be negative in some cases. Experience with isavuconazole for the treatment of Candida endophthalmitis is limited. We present a case of a 65-year-old woman with metastatic breast cancer on chemotherapy who developed Candida dubliniensis endophthalmitis with initial negative ophthalmological examination. She was treated with vitrectomy and 6 weeks of oral fluconazole. Despite vitrectomy and culture-directed antifungal treatment, management was complicated by lack of response to fluconazole and intolerance to other antifungals, necessitating the use of isavuconazole, which proved efficacious.

First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas.

BACKGROUND: GWN323 is an IgG1 monoclonal antibody (mAb) against the glucocorticoid-induced tumor necrosis factor receptor-related protein. This first-in-human, open-label phase I/Ib study aimed to investigate the safety and tolerability and to identify the recommended doses of GWN323 with/without spartalizumab, an anti-programmed cell death receptor-1 agent, for future studies. Pharmacokinetics, preliminary efficacy and efficacy biomarkers were also assessed. METHODS: Patients (aged ≥18 years) with advanced/metastatic solid tumors with Eastern Cooperative Oncology Group performance status of ≤2 were included. GWN323 (10-1500 mg) or GWN323+spartalizumab (GWN323 10-750 mg+spartalizumab 100-300 mg) were administered intravenously at various dose levels and schedules during the dose-escalation phase. Dose-limiting toxicities (DLTs) were assessed during the first 21 days in a single-agent arm and 42 days in a combination arm. Adverse events (AEs) were graded per National Cancer Institute-Common Toxicity Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors V.1.1. RESULTS: Overall, 92 patients (single-agent, n=39; combination, n=53) were included. The maximum administered doses (MADs) in the single-agent and combination arms were GWN323 1500 mg every 3 weeks (q3w) and GWN323 750 mg+spartalizumab 300 mg q3w, respectively. No DLTs were observed with single-agent treatment. Three DLTs (6%, all grade ≥3) were noted with combination treatment: blood creatine phosphokinase increase, respiratory failure and small intestinal obstruction. Serious AEs were reported in 30.8% and 34.0%, and drug-related AEs were reported in 82.1% and 77.4% of patients with single-agent and combination treatments, respectively. Disease was stable in 7 patients and progressed in 26 patients with single-agent treatment. In combination arm patients, 1 had complete response (endometrial cancer); 3, partial response (rectal cancer, adenocarcinoma of colon and melanoma); 14, stable disease; and 27, disease progression. GWN323 exhibited a pharmacokinetic profile typical of mAbs with a dose-dependent increase in the pharmacokinetic exposure. Inconsistent decreases in regulatory T cells and increases in CD8+ T cells were observed in the combination arm. Gene expression analyses showed no significant effect of GWN323 on interferon-γ or natural killer-cell signatures. CONCLUSIONS: GWN323, as a single agent and in combination, was well tolerated in patients with relapsed/refractory solid tumors. The MAD was 1500 mg q3w for single-agent and GWN323 750 mg+spartalizumab 300 mg q3w for combination treatments. Minimal single-agent activity and modest clinical benefit were observed with the spartalizumab combination. TRIAL REGISTRATION NUMBER: NCT02740270.

Tissue-specific cell-free DNA degradation quantifies circulating tumor DNA burden.

Profiling of circulating tumor DNA (ctDNA) may offer a non-invasive approach to monitor disease progression. Here, we develop a quantitative method, exploiting local tissue-specific cell-free DNA (cfDNA) degradation patterns, that accurately estimates ctDNA burden independent of genomic aberrations. Nucleosome-dependent cfDNA degradation at promoters and first exon-intron junctions is strongly associated with differential transcriptional activity in tumors and blood. A quantitative model, based on just 6 regulatory regions, could accurately predict ctDNA levels in colorectal cancer patients. Strikingly, a model restricted to blood-specific regulatory regions could predict ctDNA levels across both colorectal and breast cancer patients. Using compact targeted sequencing (<25 kb) of predictive regions, we demonstrate how the approach could enable quantitative low-cost tracking of ctDNA dynamics and disease progression.