Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B.

Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I → KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy.

The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Anthracycline Toxicity: Light at the End of the Tunnel?

Anthracycline-induced cardiotoxicity (AIC) is a serious and common side effect of anthracycline therapy. Identification of genes and genetic variants associated with AIC risk has clinical potential as a cardiotoxicity predictive tool and to allow the development of personalized therapies. In this review, we provide an overview of the function of known AIC genes identified by association studies and categorize them based on their mechanistic implication in AIC. We also discuss the importance of functional validation of AIC-associated variants in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to advance the implementation of genetic predictive biomarkers. Finally, we review how patient-specific hiPSC-CMs can be used to identify novel patient-relevant functional targets and for the discovery of cardioprotectant drugs to prevent AIC. Implementation of functional validation and use of hiPSC-CMs for drug discovery will identify the next generation of highly effective and personalized cardioprotectants and accelerate the inclusion of approved AIC biomarkers into clinical practice.

Cardio-oncology care in the era of the coronavirus disease 2019 (COVID-19) pandemic: An International Cardio-Oncology Society (ICOS) statement.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a pandemic of unprecedented proportions in the modern era because of its highly contagious nature and impact on human health and society: coronavirus disease 2019 (COVID-19). Patients with cardiovascular (CV) risk factors and established CV disease (CVD) are among those initially identified at the highest risk for serious complications, including death. Subsequent studies have pointed out that patients with cancer are also at high risk for a critical disease course. Therefore, the most vulnerable patients are seemingly those with both cancer and CVD, and a careful, unified approach in the evaluation and management of this patient population is especially needed in times of the COVID-19 pandemic. This review provides an overview of the unique implications of the viral outbreak for the field of cardio-oncology and outlines key modifications in the approach to this ever-increasing patient population. These modifications include a shift toward greater utilization of cardiac biomarkers and a more focused CV imaging approach in the broader context of modifications to typical practice pathways. The goal of this strategic adjustment is to minimize the risk of SARS-CoV-2 infection (or other future viral outbreaks) while not becoming negligent of CVD and its important impact on the overall outcomes of patients who are being treated for cancer.

Anthracyclines induce cardiotoxicity through a shared gene expression response signature.

TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.

DNA-PKcs-mediated transcriptional regulation of TOP2B drives chemoresistance in acute myeloid leukemia.

Anthracyclines, topoisomerase II enzyme poisons that cause DNA damage, are the mainstay of acute myeloid leukemia (AML) treatment. However, acquired resistance to anthracyclines leads to relapse, which currently lacks effective treatment and is the cause of poor survival in individuals with AML. Therefore, the identification of the mechanisms underlying anthracycline resistance remains an unmet clinical need. Here, using patient-derived primary cultures and clinically relevant cellular models that recapitulate acquired anthracycline resistance in AML, we have found that GCN5 (also known as KAT2A) mediates transcriptional upregulation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in AML relapse, independently of the DNA-damage response. We demonstrate that anthracyclines fail to induce DNA damage in resistant cells, owing to the loss of expression of their target enzyme, TOP2B; this was caused by DNA-PKcs directly binding to its promoter upstream region as a transcriptional repressor. Importantly, DNA-PKcs kinase activity inhibition re-sensitized AML relapse primary cultures and cells resistant to mitoxantrone, and abrogated their tumorigenic potential in a xenograft mouse model. Taken together, our findings identify a GCN5-DNA-PKcs-TOP2B transcriptional regulatory axis as the mechanism underlying anthracycline resistance, and demonstrate the therapeutic potential of DNA-PKcs inhibition to re-sensitize resistant AML relapse cells to anthracycline.

Bayesian semiparametric model for sequential treatment decisions with informative timing.

We develop a Bayesian semiparametric model for the impact of dynamic treatment rules on survival among patients diagnosed with pediatric acute myeloid leukemia (AML). The data consist of a subset of patients enrolled in a phase III clinical trial in which patients move through a sequence of four treatment courses. At each course, they undergo treatment that may or may not include anthracyclines (ACT). While ACT is known to be effective at treating AML, it is also cardiotoxic and can lead to early death for some patients. Our task is to estimate the potential survival probability under hypothetical dynamic ACT treatment strategies, but there are several impediments. First, since ACT is not randomized, its effect on survival is confounded over time. Second, subjects initiate the next course depending on when they recover from the previous course, making timing potentially informative of subsequent treatment and survival. Third, patients may die or drop out before ever completing the full treatment sequence. We develop a generative Bayesian semiparametric model based on Gamma Process priors to address these complexities. At each treatment course, the model captures subjects' transition to subsequent treatment or death in continuous time. G-computation is used to compute a posterior over potential survival probability that is adjusted for time-varying confounding. Using our approach, we estimate the efficacy of hypothetical treatment rules that dynamically modify ACT based on evolving cardiac function.

Clinicopathologic and molecular correlates to neoadjuvant chemotherapy-induced pathologic response in breast angiosarcoma.

Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior. Despite multimodality therapy, local and distant relapse rates remain high. Therefore, neoadjuvant chemotherapy (NACT) is employed to improve the R0 resection rates and survival, but its benefits remain controversial. Herein, we investigate pathologic and molecular correlates to NACT-induced histologic response in a group of 29 breast AS, 4 primary and 25 radiation-associated (RA). The two NACT regimens applied were anthracycline- and non-anthracycline-based. The pathologic response grade was defined as: I: ≤ 50%, II: 51%-90%, III: 91%-99%, and IV: 100%. An additional 45 primary AS and 102 RA-AS treated by surgery alone were included for survival comparison. The genomic landscape was analyzed in a subset of cases and compared to a cohort of AS without NACT on a paired tumor-normal targeted DNA NGS platform. All patients were females, with a median age of 31 years in primary AS and 68 years in RA-AS. All surgical margins were negative in NACT group. The NACT response was evenly divided between poor (Grades I-II; n = 15) and good responders (Grades III-IV; n = 14). Mitotic count >10/mm2 was the only factor inversely associated with pathologic response. By targeted NGS, all 10 post-NACT RA-AS demonstrated MYC amplification, while both primary AS harbored KDR mutations. TMB or other genomic alterations did not correlate with pathologic response. All four patients with Grade IV response remained free of disease. The good responders had a significantly better disease-specific survival (p = 0.04). There was no survival difference with NACT status or the NACT regimens applied. However, NACT patients with MYC-amplified tumors showed better disease-free survival (p = 0.04) compared to MYC-amplified patients without NACT. The overall survival of NACT group correlated with size >10 cm (p = 0.02), pathologic response (p = 0.04), and multifocality (p = 0.01) by univariate, while only size >10 cm (p = 0.03) remained significant by multivariate analysis.

Effect of carvedilol versus placebo on cardiac function in anthracycline-exposed survivors of childhood cancer (PREVENT-HF): a randomised, controlled, phase 2b trial.

BACKGROUND: Carvedilol improves cardiac function in patients with heart failure but remains untested as cardioprotective therapy in long-term childhood cancer survivors (ie, those who have completed treatment for childhood cancer and are in remission) at risk for heart failure due to high-dose anthracycline exposure. We aimed to evaluate the activity and safety of low-dose carvedilol for heart failure risk reduction in childhood cancer survivors at highest risk for heart failure. METHODS: PREVENT-HF was a randomised, double-blind, phase 2b trial done at 30 hospitals in the USA and Canada. Patients were eligible if they had any cancer diagnosis that resulted in at least 250 mg/m2 cumulative exposure to anthracycline by age 21 years; completed their cancer treatment at least 2 years previously; an ejection fraction of at least 50% or fractional shortening of at least 25%, or both; and bodyweight of at least 40 kg. Patients were randomly assigned (1:1) with automated computer-generated permuted block randomisation (block size of 4), stratified by age at diagnosis, time since diagnosis, and history of chest-directed radiotherapy, to carvedilol (up-titrated from 3·125 g per day to 12·5 mg per day) or placebo orally for 2 years. Participants, staff, and investigators were masked to study group allocation. The primary endpoint was to establish the effect of carvedilol on standardised left ventricular wall thickness-dimension ratio Z score (LVWT/Dz). Treatment effects were analysed with a linear mixed-effects model for normally distributed data with a linear time effect and testing the significance of treatment*time interaction in the modified intention-to-treat (mITT) cohort (ie, all randomly assigned participants who had a baseline and at least one subsequent echocardiogram measurement). Safety was assessed in the ITT population (ie, all randomly assigned participants). This trial was registered with ClinicalTrials.gov, NCT027175073, and enrolment and follow-up are complete. FINDINGS: Between July 3, 2012, and June 22, 2020, 196 participants were enrolled, of whom 182 (93%) were eligible and randomly assigned to either carvedilol (n=89) or placebo (n=93; ITT population). Median age was 24·7 years (IQR 19·6-36·6), 91 (50%) participants were female, 91 (50%) were male, and 119 (65%) were non-Hispanic White. As of data cutoff (June 10, 2022), median follow-up was 725 days (IQR 378-730). 151 (n=75 in the carvedilol group and n=76 in the placebo group) of 182 participants were included in the mITT population, among whom LVWT/Dz was similar between the two groups (-0·14 [95% CI -0·43 to 0·16] in the carvedilol group vs -0·45 [-0·77 to -0·13] in the placebo group; difference 0·31 [95% CI -0·10 to 0·73]; p=0·14). Two (2%) of 89 patients in the carvedilol group two adverse events of grade 2 or higher (n=1 shortness of breath and n=1 arthralgia) and none in the placebo group. There were no adverse events of grade 3 or higher and no deaths. INTERPRETATION: Low-dose carvedilol appears to be safe in long-term childhood cancer survivors at risk for heart failure, but did not result in significant improvement of LVWT/Dz compared with placebo. These results do not support the use of carvedilol for secondary heart failure prevention in anthracycline-exposed childhood cancer survivors. FUNDING: National Cancer Institute, Leukemia & Lymphoma Society, St Baldrick's Foundation, Altschul Foundation, Rally Foundation, American Lebanese Syrian Associated Charities.

Streptomyces extracellular vesicles are a broad and permissive antimicrobial packaging and delivery system.

Streptomyces are the primary source of bioactive specialized metabolites used in research and medicine, including many antimicrobials. These are presumed to be secreted and function as freely soluble compounds. However, increasing evidence suggests that extracellular vesicles are an alternative secretion system. We assessed environmental and lab-adapted Streptomyces (sporulating filamentous actinomycetes) and found frequent production of antimicrobial vesicles. The molecular cargo included actinomycins, anthracyclines, candicidin, and actinorhodin, reflecting both diverse chemical properties and diverse antibacterial and antifungal activity. The levels of packaged antimicrobials correlated with the level of inhibitory activity of the vesicles, and a strain knocked out for the production of anthracyclines produced vesicles that lacked antimicrobial activity. We demonstrated that antimicrobial containing vesicles achieve direct delivery of the cargo to other microbes. Notably, this delivery via membrane fusion occurred to a broad range of microbes, including pathogenic bacteria and yeast. Vesicle encapsulation offers a broad and permissive packaging and delivery system for antimicrobial specialized metabolites, with important implications for ecology and translation.IMPORTANCEExtracellular vesicle encapsulation changes our picture of how antimicrobial metabolites function in the environment and provides an alternative translational approach for the delivery of antimicrobials. We find many Streptomyces strains are capable of releasing antimicrobial vesicles, and at least four distinct classes of compounds can be packaged, suggesting this is widespread in nature. This is a striking departure from the primary paradigm of the secretion and action of specialized metabolites as soluble compounds. Importantly, the vesicles deliver antimicrobial metabolites directly to other microbes via membrane fusion, including pathogenic bacteria and yeast. This suggests future applications in which lipid-encapsulated natural product antibiotics and antifungals could be used to solve some of the most pressing problems in drug resistance.

Multicenter, Prospective, Randomized Controlled Trial of High-Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial.

BACKGROUND: Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. METHODS: In a multicenter, prospective, randomized, open-label, blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk nonrandomized patients with cardiac troponin I concentrations in the lower 2 tertiles, we hypothesized the absence of a 6-month change in left ventricular ejection fraction and tested for equivalence of ±2%. RESULTS: Between October 2017 and June 2021, 175 patients (mean age, 53 years; 87% female; 71% with breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy, respectively. After adjustment for age, pretreatment left ventricular ejection fraction, and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was -0.37% (95% CI, -3.59% to 2.85%; P=0.82). In low-risk nonrandomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3%, respectively: estimated mean difference, 2.87% (95% CI, 1.63%-4.10%; P=0.92, not equivalent). CONCLUSIONS: Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk nonrandomized patients had similar declines in left ventricular ejection fraction, bringing into question the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy need to be better defined in patients receiving high-dose anthracycline. REGISTRATION: URL: https://doi.org; Unique identifier: 10.1186/ISRCTN24439460. URL: https://www.clinicaltrialsregister.eu/ctr-search/search; Unique identifier: 2017-000896-99.

Exercise for the Prevention of Anthracycline-Induced Functional Disability and Cardiac Dysfunction: The BREXIT Study.

BACKGROUND: Breast cancer survivors treated with anthracycline-based chemotherapy (AC) have increased risk of functional limitation and cardiac dysfunction. We conducted a 12-month randomized controlled trial in 104 patients with early-stage breast cancer scheduled for AC to determine whether 12 months of exercise training (ExT) could attenuate functional disability (primary end point), improve cardiorespiratory fitness (VO2peak), and prevent cardiac dysfunction. METHODS: Women 40 to 75 years of age with stage I to III breast cancer scheduled for AC were randomized to 3 to 4 days per week aerobic and resistance ExT for 12 months (n=52) or usual care (UC; n=52). Functional measures were performed at baseline, at 4 weeks after AC (4 months), and at 12 months, comprising: (1) cardiopulmonary exercise testing to quantify VO2peak and functional disability (VO2peak ≤18.0 mL·kg-1·min-1); (2) cardiac reserve (response from rest to peak exercise), quantified with exercise cardiac magnetic resonance measures to determine changes in left and right ventricular ejection fraction, cardiac output, and stroke volume; (3) standard-of-care echocardiography-derived resting left ventricular ejection fraction and global longitudinal strain; and (4) biochemistry (troponin and BNP [B-type natriuretic peptide]). RESULTS: Among 104 participants randomized, greater study attrition was observed among UC participants (P=0.031), with 93 women assessed at 4 months (ExT, n=49; UC, n=44) and 87 women assessed at 12 months (ExT, n=49; UC, n=38). ExT attenuated functional disability at 4 months (odds ratio, 0.32 [95% CI, 0.11-0.94]; P=0.03) but not at 12 months (odds ratio, 0.27 [95% CI, 0.06-1.12]; P=0.07). In a per-protocol analysis, functional disability was prevented entirely at 12 months among participants adherent to ExT (ExT, 0% versus UC, 20%; P=0.005). Compared with UC at 12 months, ExT was associated with a net 3.5-mL·kg-1·min-1 improvement in VO2peak that coincided with greater cardiac output, stroke volume, and left and right ventricular ejection fraction reserve (P<0.001 for all). There was no effect of ExT on resting measures of left ventricular function. Postchemotherapy troponin increased less in ExT than in UC (8-fold versus 16-fold increase; P=0.002). There were no changes in BNP in either group. CONCLUSIONS: In women with early-stage breast cancer undergoing AC, 12 months of ExT did not attenuate functional disability, but provided large, clinically meaningful benefits on VO2peak and cardiac reserve. REGISTRATION: URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12617001408370.

Diversifying the anthracycline class of anti-cancer drugs identifies aclarubicin for superior survival of acute myeloid leukemia patients.

The efficacy of anthracycline-based chemotherapeutics, which include doxorubicin and its structural relatives daunorubicin and idarubicin, remains almost unmatched in oncology, despite a side effect profile including cumulative dose-dependent cardiotoxicity, therapy-related malignancies and infertility. Detoxifying anthracyclines while preserving their anti-neoplastic effects is arguably a major unmet need in modern oncology, as cardiovascular complications that limit anti-cancer treatment are a leading cause of morbidity and mortality among the 17 million cancer survivors in the U.S. In this study, we examined different clinically relevant anthracycline drugs for a series of features including mode of action (chromatin and DNA damage), bio-distribution, anti-tumor efficacy and cardiotoxicity in pre-clinical models and patients. The different anthracycline drugs have surprisingly individual efficacy and toxicity profiles. In particular, aclarubicin stands out in pre-clinical models and clinical studies, as it potently kills cancer cells, lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. Retrospective analysis of aclarubicin used as second-line treatment for relapsed/refractory AML patients showed survival effects similar to its use in first line, leading to a notable 23% increase in 5-year overall survival compared to other intensive chemotherapies. Considering individual anthracyclines as distinct entities unveils new treatment options, such as the identification of aclarubicin, which significantly improves the survival outcomes of AML patients while mitigating the treatment-limiting side-effects. Building upon these findings, an international multicenter Phase III prospective study is prepared, to integrate aclarubicin into the treatment of relapsed/refractory AML patients.

Preventing and Treating Anthracycline Cardiotoxicity: New Insights.

Anthracyclines are the cornerstone of many chemotherapy regimens for a variety of cancers. Unfortunately, their use is limited by a cumulative dose-dependent cardiotoxicity. Despite more than five decades of research, the biological mechanisms underlying anthracycline cardiotoxicity are not completely understood. In this review, we discuss the incidence, risk factors, types, and pathophysiology of anthracycline cardiotoxicity, as well as methods to prevent and treat this condition. We also summarize and discuss advances made in the last decade in the comprehension of the molecular mechanisms underlying the pathology.

Prediabetes is associated with increased cardiac events in patients with cancer who are prescribed anthracyclines.

BACKGROUND: Prediabetes, which is a precedent of overt diabetes, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in patients with cancer who are prescribed anthracycline-containing chemotherapy (ACT) is uncertain. The objective of this study was to evaluate the association of prediabetes with cardiovascular events in patients with cancer who are prescribed ACT. METHODS: The authors identified patients with cancer who received ACT from 2000 to 2019 from Clinical Data Analysis Reporting System of Hong Kong. Patients were divided into diabetes, prediabetes, and normoglycemia groups based on their baseline glycemic profile. The Primary outcome, a major adverse cardiovascular event (MACE), was the composite event of hospitalization for heart failure and cardiovascular death. RESULTS: Among 12,649 patients at baseline, 3997 had prediabetes, and 5622 had diabetes. Over median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycemia group, 358 (9.0%) in the prediabetes group, and 728 (12.9%) in the diabetes group. Compared with normoglycemia, prediabetes (adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.01-1.43) and diabetes (adjusted HR, 1.46; 95% CI, 1.24-1.70) were associated with an increased risk of MACE. In the prediabetes group, 475 patients (18%) progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR, 1.76; 95% CI, 1.31-2.36) compared with patients who remained prediabetic. CONCLUSIONS: In patients with cancer who received ACT, those who had prediabetes at baseline and those who progressed to diabetes at follow-up had an increased risk of MACE. The optimization of cardiovascular risk factor management, including prediabetes, should be considered in patients with cancer who are treated before and during ACT to reduce cardiovascular risk. PLAIN LANGUAGE SUMMARY: Patients with cancer who have preexisting diabetes have a higher risk of cardiovascular events, and prediabetes is often overlooked. In this study of 12,649 patients with cancer identified in the Clinical Data Analysis Reporting System of Hong Kong who were receiving treatment with anthracycline drugs, prediabetes was correlated with increased deaths from cardiovascular disease and/or hospitalizations for heart failure. Patients who progressed from prediabetes to diabetes within 2 years had an increased risk of combined hospitalization for heart failure and death from cardiovascular disease. These findings indicate the importance of paying greater attention to cardiovascular risk factors, including how prediabetes is managed, in patients who have cancer and are receiving chemotherapy with anthracyclines, emphasizing the need for surveillance, follow-up strategies, and consideration of prediabetes management in cancer care.

Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials.

BACKGROUND: Anthracycline-taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline-taxane regimens. METHODS: We did an individual patient-level meta-analysis of randomised trials comparing taxane regimens with versus without anthracycline, and updated our previous meta-analysis of anthracycline regimens with versus without taxane, as well as analysing 44 trials in six related comparisons. We searched databases, including MEDLINE, Embase, the Cochrane Library, and meeting abstracts to identify trials assessing anthracycline and taxane chemotherapy. Adjuvant or neoadjuvant trials were eligible if they began before Jan 1, 2012. Primary outcomes were breast cancer recurrence and cause-specific mortality. Log-rank analyses yielded first-event rate ratios (RRs) and CIs. FINDINGS: 28 trials of taxane regimens with or without anthracycline were identified, of which 23 were deemed eligible, and 15 provided data on 18 103 women. Across all 15 trials that provided individual data, recurrence rates were 14% lower on average (RR 0·86, 95% CI 0·79-0·93; p=0·0004) with taxane regimens including anthracycline than those without. Non-breast cancer deaths were not increased but there was one additional acute myeloid leukaemia case per 700 women treated. The clearest reductions in recurrence were found when anthracycline was added concurrently to docetaxel plus cyclophosphamide versus the same dose of docetaxel plus cyclophosphamide (10-year recurrence risk 12·3% vs 21·0%; risk difference 8·7%, 95% CI 4·5-12·9; RR 0·58, 0·47-0·73; p<0·0001). 10-year breast cancer mortality in this group was reduced by 4·2% (0·4-8·1; p=0·0034). No significant reduction in recurrence risk was found for sequential schedules of taxane plus anthracycline when compared with docetaxel plus cyclophosphamide (RR 0·94, 0·83-1·06; p=0·30). For the analysis of anthracycline regimens with versus without taxane, 35 trials (n=52 976) provided individual patient data. Larger recurrence reductions were seen from adding taxane to anthracycline regimens when the cumulative dose of anthracycline was the same in each group (RR 0·87, 0·82-0·93; p<0·0001; n=11 167) than in trials with two-fold higher cumulative doses of non-taxane (mostly anthracycline) in the control group than in the taxane group (RR 0·96, 0·90-1·03; p=0·27; n=14 620). Direct comparisons between anthracycline and taxane regimens showed that a higher cumulative dose and more dose-intense schedules were more efficacious. The proportional reductions in recurrence for taxane plus anthracycline were similar in oestrogen receptor-positive and oestrogen receptor-negative disease, and did not differ by age, nodal status, or tumour size or grade. INTERPRETATION: Anthracycline plus taxane regimens are most efficacious at reducing breast cancer recurrence and death. Regimens with higher cumulative doses of anthracycline plus taxane provide the greatest benefits, challenging the current trend in clinical practice and guidelines towards non-anthracycline chemotherapy, particularly shorter regimens, such as four cycles of docetaxel-cyclophosphamide. By bringing together data from almost all relevant trials, this meta-analysis provides a reliable evidence base to inform individual treatment decisions, clinical guidelines, and the design of future clinical trials. FUNDING: Cancer Research UK, UK Medical Research Council.

Neoadjuvant anthracycline-based (5-FEC) or anthracycline-free (docetaxel/carboplatin) chemotherapy plus trastuzumab and pertuzmab in HER2 + BC patients according to their TOP2A: a multicentre, open-label, non-randomized phase II trial.

PURPOSE: Previous studies have reported the benefit of dual HER2-targeting combined to neoadjuvant chemotherapy in HER2-amplified breast cancer (HER2 + BC). Moreover, besides the cardiac toxicity following their association to Trastuzumab, anthracyclines chemotherapy may not profit all patients. The NeoTOP study was designed to evaluate the complementary action of Trastuzumab and Pertuzumab, and the relevance of an anthracycline-based regimen according to TOP2A amplification status. METHODS: Open-label, multicentre, phase II study. Eligible patients were aged ≥ 18 with untreated, operable, histologically confirmed HER2 + BC. After centralized review of TOP2A status, TOP2A-amplified (TOP2A+) patients received FEC100 for 3 cycles then 3 cycles of Trastuzumab (8 mg/kg then 6 mg/kg), Pertuzumab (840 mg/kg then 420 mg/kg), and Docetaxel (75mg/m2 then 100mg/m2). TOP2A-not amplified (TOP2A-) patients received 6 cycles of Docetaxel (75mg/m2) and Carboplatin (target AUC 6 mg/ml/min) plus Trastuzumab and Pertuzumab. Primary endpoint was pathological Complete Response (pCR) using Chevallier's classification. Secondary endpoints included pCR (Sataloff), Progression-Free Survival (PFS), Overall Survival (OS), and toxicity. RESULTS: Out of 74 patients, 41 and 33 were allocated to the TOP2A + and TOP2A- groups respectively. pCR rates (Chevallier) were 74.4% (95%CI: 58.9-85.4) vs. 71.9% (95%CI: 54.6-84.4) in the TOP2A + vs. TOP2A- groups. pCR rates (Sataloff), 5-year PFS and OS were 70.6% (95%CI: 53.8-83.2) vs. 61.5% (95%CI: 42.5-77.6), 82.4% (95%CI: 62.2-93.6) vs. 100% (95%CI: 74.1-100), and 90% (95%CI: 69.8-98.3) vs. 100% (95%CI: 74.1-100). Toxicity profile was consistent with previous reports. CONCLUSION: Our results showed high pCR rates with Trastuzumab and Pertuzumab associated to chemotherapy. They were similar in TOP2A + and TOP2A- groups and the current role of neoadjuvant anthracycline-based chemotherapy remains questioned. TRIAL REGISTRATION NUMBER: NCT02339532 (registered on 14/12/14).

Taxane combined with lobaplatin or anthracycline for neoadjuvant chemotherapy of triple-negative breast cancer: a randomized, controlled, phase II study.

BACKGROUND: Previous studies have shown that the addition of platinum to neoadjuvant chemotherapy (NAC) improved outcomes for patients with triple-negative breast cancer (TNBC). However, no studies have assessed the efficacy and safety of the combination of taxane and lobaplatin. In this study, we conducted a randomized controlled phase II clinical study to compare the efficacy and safety of taxane combined with lobaplatin or anthracycline. METHODS: We randomly allocated patients with stage I-III TNBC into Arm A and Arm B. Arm A received six cycles of taxane combined with lobaplatin (TL). Arm B received six cycles of taxane combined with anthracycline and cyclophosphamide (TEC) or eight cycles of anthracycline combined with cyclophosphamide and sequential use of taxane (EC-T). Both Arms underwent surgery after NAC. The primary endpoint was the pathologic complete response (pCR). Secondary endpoints were event-free survival (EFS), overall survival (OS), and safety. RESULTS: A total of 103 patients (51 in Arm A and 52 in Arm B) were assessed. The pCR rate of Arm A was significantly higher than that of Arm B (41.2% vs. 21.2%, P = 0.028). Patients with positive lymph nodes and low neutrophil-to-lymphocyte ratio (NLR) benefited significantly more from Arm A than those with negative lymph nodes and high NLR (Pinteraction = 0.001, Pinteraction = 0.012, respectively). There was no significant difference in EFS (P = 0.895) or OS (P = 0.633) between the two arms. The prevalence of grade-3/4 anemia was higher in Arm A (P = 0.015), and the prevalence of grade-3/4 neutropenia was higher in Arm B (P = 0.044). CONCLUSIONS: Neoadjuvant taxane plus lobaplatin has shown better efficacy than taxane plus anthracycline, and both regimens have similar toxicity profiles. This trial may provide a reference for a better combination strategy of immunotherapy in NAC for TNBC in the future.

Mid- and long-term risk of atrial fibrillation among breast cancer surgery survivors.

BACKGROUND: The risk of incident atrial fibrillation (AF) among breast cancer survivors, especially for younger women, and cancer treatment effects on the association remain unclear. This study aimed to investigate the risk of AF among breast cancer survivors and evaluate the association by age group, length of follow-up, and cancer treatment. METHODS: Using data from the Korean Health Insurance Service database (2010-2017), 113,232 women newly diagnosed with breast cancer (aged ≥ 18 years) without prior AF history who underwent breast cancer surgery were individually matched 1:5 by birth year to a sample female population without cancer (n = 566,160) (mean[SD] follow-up, 5.1[2.1] years). Sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs) considering death as a competing risk were estimated, adjusting for sociodemographic factors and cardiovascular/non-cardiovascular comorbidities. RESULTS: BCS had a slightly increased AF risk compared to their cancer-free counterparts (sHR 1.06; 95% CI 1.00-1.13), but the association disappeared over time. Younger BCS (age < 40 years) had more than a 2-fold increase in AF risk (sHR 2.79; 95% CI 1.98-3.94), with the association remaining similar over 5 years of follow-up. The increased risk was not observed among older BCS, especially those aged > 65 years. Use of anthracyclines was associated with increased AF risk among BCS (sHR 1.57; 95% CI 1.28-1.92), which was more robust in younger BCS (sHR 1.94; 95% CI 1.40-2.69 in those aged ≤ 50 years). CONCLUSIONS: Our findings suggest that younger BCS had an elevated risk of incident AF, regardless of the length of follow-up. Use of anthracyclines may be associated with increased mid-to-long-term AF risk among BCS.

Controversies on chemotherapy for early HR+/HER2- breast cancer: the role of anthracyclines and dose intensification.

PURPOSE OF REVIEW: Use of adjuvant chemotherapy significantly reduces the risk of recurrence and improves overall survival (OS) in patients with early-stage breast cancer. However, few data are available on the efficacy of different adjuvant chemotherapy regimens and schedules in patients with hormone receptor positive/HER2-negative (HR+/HER2-) breast cancer. We aim to summarize the available evidence on the efficacy of adjuvant anthracycline-based chemotherapy and of the dose-dense schedule in this specific patient population. Moreover, current controversies in the management of patients with early-stage HR+/HER2- breast cancer are discussed. RECENT FINDINGS: Patient-level meta-analysis evaluating the role of the addition of an anthracycline to taxane-based chemotherapy showed that recurrence rate was lower among patients receiving anthracycline-based treatment.Patient-level meta-analysis evaluating the role of different schedules of chemotherapy administration showed that the use of adjuvant dose-dense chemotherapy is associated with significant reduction in breast cancer recurrences and breast cancer mortality. Less evidence is available in the neoadjuvant setting. SUMMARY: For patients with high-risk HR+/HER2- breast cancer, (neo) adjuvant anthracycline and taxane-based chemotherapy, and a dose-dense regimen should still be considered the standard of care. However, in patients with intermediate risk breast cancer candidates to chemotherapy, anthracycline-free regimens could be considered the preferred treatment option.