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Purpose: Neoadjuvant chemotherapy (NAC) is increasingly used in breast cancer. Predictive modeling is useful in predicting pathologic complete response (pCR) to NAC. We test machine learning (ML) models to predict pCR in breast cancer and explore methods of handling missing data., Methods: Four hundred and ninety-nine patients with breast cancer treated with NAC in two centers in Singapore (National Cancer Centre Singapore [NCCS] and KK Hospital) between January 2014 and December 2017 were included. Eleven clinical features were used to train five different ML models. Listwise deletion and imputation were evaluated on handling missing data. Model performance was evaluated by AUC and calibration (Brier score). Feature importance from the best performing model in the external testing data set was calculated using Shapley additive explanations., Results: Seventy-two (24.6%), 18 (24.7%), and 31 (24.8%) patients attained pCR in NCCS training, NCCS testing, and KK Women's and Children's Hospital (KKH) testing data sets, respectively. The random forest (RF) base and imputed models have the highest AUCs in the KKH cohort of 0.794 (95% CI, 0.709 to 0.873) and 0.795 (95% CI, 0.706 to 0.871), respectively, and were the best calibrated with the lowest Brier score. No statistically significant difference was noted between AUCs of the base and imputed models in all data sets. The imputed model had a larger positive predictive value (PPV; 98.2% v 95.1%) and negative predictive value (NPV; 96.7% v 90.0%) than the base model in the KKH data set. Estrogen receptor intensity, human epidermal growth factor 2 intensity, and age at diagnosis were the three most important predictors., Conclusion: ML, particularly RF, demonstrates reasonable accuracy in pCR prediction after NAC. Imputing missing fields in the data can improve the PPV and NPV of the pCR prediction model.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

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 PRS overall 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 (PRS ER-pos ) and ER-negative weighted PRS (PRS ER-neg )., Conclusion: BC PRS was not strongly associated with chemotherapy-induced neutropenia or FNc.

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/m 2 ., Results: In our Asian patient cohort, dosing at 40 mg/m 2 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 T max 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/m 2 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., Competing Interests: Conflict of interest statement: The author declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: D.S.P.T. received consultancy fees from AstraZeneca, Roche, MSD, Merck Serono, Tessa Therapeutics, Eisai and Genmab; D.S.P.T. received research funding from AstraZeneca, Bayer and Karyopharm. V.H. received consultancy fees for AstraZeneca, Pfizer, DKSH and Novartis; Stock Ownership: Asian Microbiome Library (AMiLi); the sponsor had no involvement in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; or the decision to submit the manuscript for publication., (© The Author(s), 2022.)

Background: Socioeconomic status (SES) is likely to affect survival in breast cancer patients. Housing value is a reasonable surrogate for SES in Singapore where most residents own their own homes, which could be public (subsidised) or private housing. We evaluated effects of housing value and enhanced medical subsidies on patients' presentation, treatment choices, compliance and survival in a setting of good access to healthcare., Methods: A retrospective analysis of breast cancer patients treated in a tertiary hospital cluster from 2000 to 2016 was performed. Individual-level Housing value Index (HI) was derived from each patient's address and then grouped into 3 tiers: HI(high)(minimal subsidy), HI(med)(medium subsidy) and HI(low)(high subsidy). Cox regression was performed to evaluate the associations between overall survival (OS) and cancer-specific survival (CSS) with HI and various factors., Findings: We studied a multiracial cohort of 15,532 Stage 0-IV breast cancer patients. Median age was 53.7 years and median follow-up was 7.7 years. Patients with lower HI presented with more advanced disease and had lower treatment compliance. On multivariable analysis, compared to HI(high) patients, HI(med) patients had decreased OS (HR=1.14, 95% CI 1.05-1.23) and CSS (HR=1.15, 95% CI 1.03-1.27), and HI(low) patients demonstrated reduced OS (HR=1.16, 95% CI 1.01-1.33). Ten-year non-cancer mortality was higher in lower HI-strata. Enhanced medical subsidy approximately halved treatment noncompliance rates but its receipt was not an independent prognostic factor for survival., Interpretation: Despite good healthcare access, lower-HI patients have poorer survival from both cancer and non-cancer causes, possibly due to delayed health-seeking and poorer treatment compliance. Enhanced subsidies may mitigate socioeconomic disadvantages., Funding: None., Competing Interests: We declare no competing interests., (© 2020 The Author(s). Published by Elsevier Ltd.)

Introduction: RET rearrangements are an emerging targetable oncogenic fusion driver in NSCLC. However, the natural history of disease and activity of different classes of systemic therapy remain to be defined. Furthermore, molecular testing for RET is not yet routine, and the optimal method of testing is unclear. We present a comparative analysis of molecular profiling with fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) and treatment outcomes., Methods: This study was a retrospective analysis of patients treated at the National Cancer Centre Singapore. Baseline demographics and treatment outcomes were collected., Results: A total of 64 patients were included, with a median age of 62 years (range: 25-85), 56% were women, 77% were of Chinese ethnicity, 95% had adenocarcinoma, and 69% were never smokers. RET rearrangement was detected by FISH in 30 of 34 patients (88%), NGS in 40 of 43 patients (93%), and with discordant results in seven of 13 patients (54%) tested with both methods. Of 61 patients with stage IIIB/IV or recurrent disease, prevalence of central nervous system metastases was 31% and 92% received palliative systemic therapy. Overall survival was prolonged in patients treated with a selective RET tyrosine kinase inhibitor versus untreated patients (median 49.3 versus 15.3 mo; hazard ratio [HR]: 0.16, 95% confidence interval [CI]: 0.06-0.40, p < 0.001). However, it was not different in patients treated with immunotherapy versus untreated patients (median 37.7 versus 49.3 mo; HR: 1.30, 95% CI: 0.53-3.19, p = 0.53). Overall survival was also prolonged in patients with CCDC6-RET fusion versus those with KIF5B-RET fusion (median 113.5 versus 37.7 mo; HR: 0.12, 95% CI: 0.04-0.38, p = 0.009)., Conclusions: In RET-rearranged NSCLC, selective RET tyrosine kinase inhibitor therapy is associated with improved survival outcomes, especially in patients with CCDC6-RET fusion. However, immunotherapy has poor efficacy. NGS and FISH testing methods may also result in substantial discordance., (Copyright © 2020. Published by Elsevier Inc.)

Background: Cancer-related fatigue (CRF) is a debilitating condition which commonly affects cancer survivors. The management of CRF remains a challenge due to the lack of effective pharmacological interventions. Traditional Chinese medicine (TCM) could be a potential therapeutic option for CRF. The modified Xiang Bei Yang Rong Tang (XBYRT) is a TCM herbal decoction, formulated to improve fatigue symptoms in cancer survivors. This clinical trial aims to evaluate the efficacy and safety of XBYRT in improving CRF and quality of life (QOL) of cancer survivors., Methods: This is a single centre, randomized, double-blind, placebo-controlled, parallel trial. Eighty cancer survivors will be recruited and randomized to receive the XBYRT or placebo decoction, in a ratio of 1:1. Participants will consume the XBYRT/placebo decoction daily for 8 weeks and undergo assessments at baseline and 4, 8 and 10 weeks after baseline. The participants will be assessed for patient-reported outcomes (PRO), blood biomarkers and adverse events at each time point. The primary outcome is the overall health and QOL status, at 8 weeks follow-up. The secondary outcomes are the effects of XBYRT on fatigue levels, cancer-related cognitive impairment and QOL, as assessed by PRO. The incidence of adverse events and the effects of the XBYRT decoction on blood biomarkers associated with CRF will also be evaluated., Discussion: Efficacy and safety outcomes from this trial will provide important clinical data to guide future large-scale randomized controlled trials, and the evaluation of the objective blood biomarkers can help to delineate the biological mechanisms of CRF., Trial Registration Number: ClinicalTrials.gov NCT04104113 . Registered on 26 September 2019.

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.

The ensuing COVID-19 pandemic poses unprecedented and daunting challenges to the routine delivery of oncological and supportive care to patients with breast cancer. Considerations include the infective risk of patients who are inherently immunosuppressed from their malignancy and therapies, long-term oncological outcomes from the treatment decisions undertaken during this extraordinary period, and diverted healthcare resources to support a coordinated whole-of-society outbreak response. In this review, we chronicle the repercussions of the COVID-19 outbreak on breast cancer management in Singapore and describe our approach to triaging and prioritising care of breast tumours. We further propose adaptations to established clinical processes and practices across the different specialties involved in breast oncology, with references to the relevant evidence base or expert consensus guidelines. These recommendations have been developed within the unique context of Singapore's public healthcare sector. They can serve as a resource to guide breast cancer management for future contingencies in this city-state, while certain elements therein may be extrapolatable to other medical systems during this global public health emergency.

Multiomic analyses have shed light upon the molecular heterogeneity and complexity of triple-negative breast cancers (TNBCs). With increasing recognition that TNBC is not a single disease entity but encompasses different disease subtypes, a one-size-fits-all treatment paradigm has become obsolete. In this context, the inhibition of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and androgen receptor (AR) signaling pathways have emerged as potential therapeutic strategies against selected tumors. In this paper, we reviewed the preclinical rationale, predictive biomarkers, efficacy, and safety data from early phase trials, and the future directions for these two biomarker-directed treatment approaches in TNBC., Competing Interests: Conflicts of interest statement: Jack J Chan: Honoraria; Merck Sharp & Dohme, Eisai, AstraZeneca, Novartis; Consulting or Advisory Role, Pfizer; Research Funding, OncoQuest; Travel, Accommodations, Expenses, AstraZeneca, Celgene. Tira JY Tan: Consulting or Advisory Role; Roche, Novartis, Eli Lily; Research Funding; AstraZeneca; Travel, Accommodations, Expenses, Eisai. Rebecca A Dent: Honoraria; AstraZeneca, Lilly, Pfizer, Roche/Genentech; Consulting or Advisory Role; AstraZeneca, Eisai, Merck, Novartis, Pfizer, Roche; Travel, Accommodations, Expenses; Amgen, Merck, Pfizer, Roche., (© The Author(s), 2019.)

Cancer-related cognitive impairment (CRCI) adversely affects cancer patients. We had previously demonstrated that the BDNF Val66Met genetic polymorphism is associated with lower odds of subjective CRCI in the multitasking and verbal ability domains among breast cancer patients receiving chemotherapy. To further assess our previous findings, we evaluated the association of BDNF Val66Met polymorphism with subjective and objective CRCI in a temporally separate cohort of patients and pooled findings from both the original (n = 145) and current (n = 193) cohorts in a meta-analysis. Subjective CRCI was assessed using FACT-Cog. Objective CRCI was evaluated using computerized neuropsychological tests. Genotyping was carried out using Sanger sequencing. The association of BDNF Val66Met genotypes and CRCI was examined with logistic regression. A fixed-effect meta-analysis was conducted using the inverse variance method. In the meta-analysis (n = 338), significantly lower odds of CRCI were associated with Met allele carriers based on the global FACT-Cog score (OR = 0.52, 95% CI 0.29-0.94). Furthermore, Met allele carriers were at lower odds of developing impairment in the domains of memory (OR = 0.34, 95% CI: 0.17-0.70), multitasking (OR = 0.33, 95% CI: 0.18-0.59), and verbal ability (OR = 0.46, 95% CI: 0.24-0.88). Consistent with the previous study, lower odds of subjective CRCI among patients with the BDNF Met allele was observed after adjusting for potential confounders in the multitasking (OR = 0.30, 95% CI: 0.14-0.67) domain. In conclusion, carriers of the BDNF Met allele were protected against global subjective CRCI, particularly in the domains of memory, multitasking, and verbal ability. Our findings further contribute to the understanding of CRCI pathophysiology.

A 45-year-old woman presented to the emergency department with jaundice of 2 weeks' duration. This was associated with mahogany seed extract (Skyfruit supplement) consumption for 6 months prior to admission. Examination was normal apart from scleral icterus and grade 2 encephalopathy. Liver function tests showed a hepatocellular pattern of derangement: alanine transaminase, 1267 U/L (10-36); aspartatetransaminase, 1255 U/L (10-30); alkaline phosphatase, 124 U/L (22-104); bilirubin, 258 µmol/L (3-21) with a prolonged prothrombin time of 16.8 s (9.2-11.0). Viral hepatitis work-up was largely unremarkable and liver biopsy showed moderate inflammatory infiltrates (mostly lymphocytic with scattered eosinophils) in the periportal region and lobule with bridging necrosis, favouring drug-induced liver injury. Withdrawal of the drug resulted in normalisation of liver function., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

The working immunohistochemical definition of triple-negative breast cancer (TNBC) is admittedly reductionist and has only limited usefulness for informing oncologists about therapeutic decisions beyond chemotherapy. Early molecular taxonomies of TNBC based heavily on gene expression profiling, which is not readily available in the clinic today, do not necessarily encompass other molecular targets already incorporated into rationally designed clinical trials. We state that it is possible to delineate five subgroups of TNBC relevant to present-day clinical practice and cover the evidence that lends credence to emerging biomarker-directed treatment strategies for each subgroup.

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.