Characteristics and Outcomes of a Single-Centre Cohort of Adult Congenital Heart Disease Patients Referred for Heart Transplant.

BACKGROUND: Adult congenital heart disease (ACHD) services increasingly encounter heart failure (HF) in the ageing ACHD population. Optimal timing of referral for heart transplant (HTx) evaluation in this heterogeneous population is complex and ill-defined. We aim to outline the characteristics and outcomes of ACHD patients referred for HTx from a large Australian ACHD centre. METHOD: Retrospective review of ACHD patients referred for HTx from a primary ACHD centre (1992-2021). Database analysis of patient demographics, characteristics, wait-listing, and transplantation outcomes was performed. RESULTS: A total of 45 patients (mean age 37±9.9 years old; 69% male) were referred for HTx with a mean follow-up of 5.9±6.3 years. Of these, 22 of 45 (49%) were listed and transplanted, including one heart-lung transplant. The commonest diagnosis was dextro-transposition of the great arteries (13/45, 29%). Most patients, 33 of 45 (73.3%) had undergone at least one cardiac surgery in childhood. Indications for HTx referral included HF in 34 of 45 (75%), followed by pulmonary hypertension in 7 of 45 (11%). Median transplant wait-list time was 145 days (interquartile range, 112-256). Of the 23 patients not wait-listed, the reasons included clinical stability in 13 of 45 (29%), psychosocial factors in 2 of 45 (4.4%) and prohibitive surgical risk, including multiorgan dysfunction, in 8 of 45 (17.7%). Transplant was of a single organ in most, 21 of 22 (95.5%). Overall mortality was 5 of 22 (22.7%) in those after HTx, and 14 of 23 (60.9%) in those not listed (p=0.0156). CONCLUSIONS: Increasingly, ACHD patients demonstrate the need for advanced HF treatments. HTx decision-making is complex, and increased mortality is seen in those not wait-listed. Ultimately, the referral of ACHD patients for HTx is underpinned by local decision-making and experience, wait-list times and outcomes.

Non-ischaemic dilated cardiomyopathy: recognising the genetic links.

The landscape of genetically related cardiac disease continues to evolve. Heritable genetic variants can be a primary cause of familial or sporadic dilated cardiomyopathy (DCM). There is also increasing recognition that genetic variation is an important determinant of susceptibility to acquired causes of DCM. Genetic forms of DCM can show a wide variety of phenotypic manifestations. Identifying patients who are most likely to benefit from genetic testing is paramount. The objective of this review is to highlight the importance of recognising genetic DCM, key genotype-phenotype correlations and the value of genetic testing in clinical management for both the individual and their family. This is likely to become more relevant as management strategies continue to be refined with genotype-specific recommendations and disease-modifying therapies.

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.

BACKGROUND: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. METHODS: An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated. RESULTS: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. CONCLUSIONS: In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.

Defining cardiac involvement in idiopathic inflammatory myopathies: a systematic review.

OBJECTIVE: Recent advances in cardiac MRI (CMR) and other diagnostic techniques have made it easier to identify subclinical cardiac inflammation and dysfunction in the idiopathic inflammatory myopathies (IIM). Herein, we systematically review the literature regarding cardiac involvement in IIM. METHODS: We searched Medline and EMBASE from 1990 to 2020 using keywords related to IIM and cardiac disease. We included English language studies in adults with any immune-mediated, inflammatory muscle pathology. RESULTS: We identified 10 425 potentially relevant abstracts, of which 29 were included. Most frequently these included patients with PM or DM without symptomatic myocarditis. Five categories of cardiac investigation were used in these patients: cardiac enzyme testing, ECG, transthoracic echocardiography, CMR and nuclear medicine testing. Patients with clinical myocarditis had universally abnormal cardiac troponin levels and ECG. Elevated cardiac troponin T was more common than cardiac troponin I and may correlate with disease activity, whereas cardiac troponin I was more specific for cardiac involvement. Non-specific ECG changes were common. The major finding on transthoracic echocardiography was abnormal ejection fraction. Gross systolic dysfunction was unusual, but subclinical systolic dysfunction was reported in several studies. Abnormal diastolic function was common and may be associated with disease duration. Late gadolinium enhancement (reflecting regional necrosis or scarring) and abnormal myocardial mapping parameters (reflecting myocardial inflammation, fibrosis and oedema) were frequently identified on CMR, suggesting significant subclinical myocardial pathology (despite typically normal ejection fraction). CONCLUSION: Abnormal cardiac investigations are commonly found in asymptomatic IIM patients, which has potential prognostic and treatment implications.

Familial Dilated Cardiomyopathy.

Advances in human genome sequencing have re-invigorated genetics studies of dilated cardiomyopathy (DCM), facilitating genetic testing and clinical applications. With a range of genetic testing options now available, new challenges arise for data interpretation and identifying single pathogenic variants from the many thousands of rare variants present in every individual. There is accumulating evidence that genetic factors have an important role in the pathogenesis of DCM. However, although more than 100 genes have been implicated to date, the sensitivity of genetic testing, even in familial disease, is only ∼25-40%. As more patients are genotyped, nuanced information about disease phenotypes is emerging including variability in age of onset and penetrance of DCM, as well as additional cardiac and extra-cardiac features. Genotype-phenotype correlations have also identified a subset of genes that can be highly arrhythmogenic or show frequent progression to heart failure. Recognition of variants in these genes is important as this may impact on the timing of implantable cardioverter-defibrillators or heart transplantation. Finding a causative variant in a patient with DCM allows predictive testing of family members and provides an opportunity for preventative intervention. Diagnostic imaging modalities such as speckle-tracking echocardiography and cardiac magnetic resonance imaging are increasingly being used to detect and monitor pre-clinical ventricular dysfunction in asymptomatic variant carriers. Although there are several examples of successful genotype-based therapy, optimal strategies for implementation of precision medicine in familial DCM remain to be determined. Identification of modifiable co-morbidities and lifestyle factors that exacerbate or protect against DCM development in genetically-predisposed individuals remains a key component of family management.

Arrhythmic Genotypes in Familial Dilated Cardiomyopathy: Implications for Genetic Testing and Clinical Management.

Cardiac arrhythmias are frequently seen in patients with dilated cardiomyopathy (DCM) and can precipitate heart failure and death. In patients with non-ischaemic DCM, evidence for the benefit of an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death has recently been questioned. Algorithms devised to identify high-risk individuals who might benefit most from ICD implantation have focussed on clinical criteria with little attention paid to the underlying aetiology of DCM. Malignant ventricular arrhythmias often occur as a nonspecific consequence of DCM but can also be a primary manifestation of disease in heritable forms of DCM and may precede DCM onset. We undertook a literature search and identified 11 genes that have been associated with DCM and ventricular arrhythmias in multiple kindreds. Many of these genes fall into a diagnostic grey zone between left-dominant arrhythmogenic right ventricular cardiomyopathy and arrhythmic DCM. Genes associated predominantly with arrhythmic DCM included LMNA and SCN5A, as well as the more recently-reported DCM disease genes, RBM20, FLNC, and TTN. Recognition of arrhythmic DCM genotypes is important, as this may impact on clinical management. In particular, prophylactic ICD implantation and early referral for heart transplantation may be indicated in genotype-positive individuals. Collectively, these findings argue in favour of including genetic testing in standard-of-care management of familial DCM. Further studies in genotyped patient cohorts are required to establish the long-term health and economic benefits of this strategy.

Achromobacter cluster related to COVID-19 supply chain issues.

Isolation of an unusual organism, Achromobacter xylosoxidans, from 2 cardiac surgical patients on the same day prompted an investigation to search for cases and cause. An extensive review demonstrated a pseudo-outbreak related to practices to conserve laboratory saline due to short supply resulting from supply chain shortage from the coronavirus disease 2019 pandemic.

Pregnancy in women with dilated cardiomyopathy genetic variants.

INTRODUCTION AND OBJECTIVES: Limited information is available on the safety of pregnancy in patients with genetic dilated cardiomyopathy (DCM) and in carriers of DCM-causing genetic variants without the DCM phenotype. We assessed cardiac, obstetric, and fetal or neonatal outcomes in this group of patients. METHODS: We studied 48 women carrying pathogenic or likely pathogenic DCM-associated variants (30 with DCM and 18 without DCM) who had 83 pregnancies. Adverse cardiac events were defined as heart failure (HF), sustained ventricular tachycardia, ventricular assist device implantation, heart transplant, and/or maternal cardiac death during pregnancy, or labor and delivery, and up to the sixth postpartum month. RESULTS: A total of 15 patients, all with DCM (31% of the total cohort and 50% of women with DCM) experienced adverse cardiac events. Obstetric and fetal or neonatal complications were observed in 14% of pregnancies (10 in DCM patients and 2 in genetic carriers). We analyzed the 30 women who had been evaluated before their first pregnancy (12 with overt DCM and 18 without the phenotype). Five of the 12 (42%) women with DCM had adverse cardiac events despite showing NYHA class I or II before pregnancy. Most of these women had a history of cardiac events before pregnancy (80%). Among the 18 women without phenotype, 3 (17%) developed DCM toward the end of pregnancy. CONCLUSIONS: Cardiac complications during pregnancy and postpartum were common in patients with genetic DCM and were primarily related to HF. Despite apparently good tolerance of pregnancy in unaffected genetic carriers, pregnancy may act as a trigger for DCM onset in a subset of these women.

Safe lists for medications in pregnancy: inadequate evidence base and inconsistent guidance from Web-based information, 2011.

PURPOSE: Medication use during pregnancy is common and increasing. Women are also increasingly getting healthcare information from sources other than their physicians. METHODS: This report summarizes an environmental scan that identified 25 active Internet sites that list medications reported to be safe for use in pregnancy and highlights the inadequate evidence base and inconsistent guidance provided by these sites. RESULTS: These lists included 245 different products, of which 103 unique components had been previously evaluated in terms of fetal risk by the Teratogen Information System (TERIS), a resource that assesses risk of birth defects after exposure under usual conditions by consensus of clinical teratology experts. For 43 (42%) of the 103 components that were listed as 'safe' on one or more of the Internet sites surveyed, the TERIS experts were unable to determine the fetal risk based on published scientific literature. For 40 (93%) of these 43, either no data were available to assess human fetal risk or the available data were limited. CONCLUSIONS: Women who see a medication on one of these 'safe' lists would be led to believe that there is no increased risk of birth defects resulting from exposure. Thus, women are being reassured that fetal exposure to these medications is safe even though a sufficient evidence base to determine the relative safety or risk does not exist.

Phenotyping heart failure by genetics and associated conditions.

Heart failure is a highly heterogeneous disease, and genetic testing may allow phenotypic distinctions that are incremental to those obtainable from imaging. Advances in genetic testing have allowed for the identification of deleterious variants in patients with specific heart failure phenotypes (dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and hypertrophic cardiomyopathy), and many of these have specific treatment implications. The diagnostic yield of genetic testing in heart failure is modest, and many rare variants are associated with incomplete penetrance and variable expressivity. Environmental factors and co-morbidities have a large role in the heterogeneity of the heart failure phenotype. Future endeavours should concentrate on the cumulative impact of genetic polymorphisms in the development of heart failure.

Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.

Background: As availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings. Methods: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. Results: For 36/65 gene-disease pairs, loss-of-function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using CardiacG2P as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. Conclusions: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is pre-requisite for scalable genomic testing.

Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.

BACKGROUND: As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. METHODS: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. RESULTS: For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. CONCLUSIONS: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing.

Impact of increasing inter-pregnancy interval on maternal and infant health.

Short inter-pregnancy intervals (IPIs) have been associated with adverse maternal and infant health outcomes in the literature. However, many studies in this area have been lacking in quality and appropriate control for confounders known to be associated with both short IPIs and poor outcomes. The objective of this systematic review was to assess this relationship using more rigorous criteria, based on GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. We found too few higher-quality studies of the impact of IPIs (measured as the time between the birth of a previous child and conception of the next child) on maternal health to reach conclusions about maternal nutrition, morbidity or mortality. However, the evidence for infant effects justified meta-analyses. We found significant impacts of short IPIs for extreme preterm birth [<6 m adjusted odds ratio (aOR): 1.58 [95% confidence interval (CI) 1.40, 1.78], 6-11 m aOR: 1.23 [1.03, 1.46]], moderate preterm birth (<6 m aOR: 1.41 [1.20, 1.65], 6-11 m aOR: 1.09 [1.01, 1.18]), low birthweight (<6 m aOR: 1.44 [1.30, 1.61], 6-11 m aOR: 1.12 [1.08, 1.17]), stillbirth (aOR: 1.35 [1.07, 1.71] and early neonatal death (aOR: 1.29 [1.02, 1.64]) outcomes largely in high- and moderate-income countries. It is likely these effects would be greater in settings with poorer maternal health and nutrition. Future research in these settings is recommended. This is particularly important in developing countries, where often the pattern is to start childbearing at a young age, have all desired children quickly and then control fertility through permanent contraception, thereby contracting women's fertile years and potentially increasing their exposure to the ill effects of very short IPIs.

The impact of early age at first childbirth on maternal and infant health.

The objective of this review was to assess whether early age at first childbirth is associated with increased risk of poor pregnancy outcomes. Early age at childbirth is variously defined in studies of its effect on maternal and infant health. In this systematic review, we limit analysis to studies of at least moderate quality that examine first births among young mothers, where young maternal age is defined as low gynaecological age (≤ 2 years since menarche) or as a chronological age ≤ 16 years at conception or delivery. We conduct meta-analyses for specific maternal or infant health outcomes when there are at least three moderate quality studies that define the exposure and outcome in a similar manner and provide odds ratios or risk ratios as their effect estimates. We conclude that the overall evidence of effect for very young maternal age (<15 years or <2 years post-menarche) on infant outcomes is moderate; that is, future studies are likely to refine the estimate of effect or precision but not to change the conclusion. Evidence points to an impact of young maternal age on low birthweight and preterm birth, which may mediate other infant outcomes such as neonatal mortality. The evidence that young maternal age increases risk for maternal anaemia is also fairly strong, although information on other nutritional outcomes and maternal morbidity/mortality is less clear. Many of the differences observed among older teenagers with respect to infant outcomes may be because of socio-economic or behavioural differences, although these may vary by country/setting. Future, high quality observational studies in low income settings are recommended in order to address the question of generalisability of evidence. In particular, studies in low income countries need to consider low gynaecological age, rather than simply chronological age, as an exposure. As well, country-specific studies should measure the minimum age at which childbearing for teens has similar associations with health as childbearing for adults. This 'tipping point' may vary by the underlying physical and nutritional health of girls and young women.

Arrhythmic Phenotypes Are a Defining Feature of Dilated Cardiomyopathy-Associated SCN5A Variants: A Systematic Review.

BACKGROUND: Variants in the SCN5A gene, that encodes the cardiac sodium channel, Nav1.5, are associated with a highly arrhythmogenic form of dilated cardiomyopathy (DCM). Our aim was to review the phenotypes, natural history, functional effects, and treatment outcomes of DCM-associated rare SCN5A variants. METHODS: A systematic review of reported DCM-associated rare SCN5A variants was undertaken using PubMed and Embase. RESULTS: Eighteen SCN5A rare variants in 29 families with DCM (173 affected individuals) were identified. Eleven variants had undergone experimental evaluation, with 7 of these resulting in increased sustained current flow during the action potential (eg, increased window current) and at resting membrane potentials (eg, creation of a new gating pore current). These variants were located in transmembrane voltage-sensing domains and had a consistent phenotype characterized by frequent multifocal narrow and broad complex ventricular premature beats (VPB; 72% of affected relatives), ventricular arrhythmias (33%), atrial arrhythmias (32%), sudden cardiac death (13%), and DCM (56%). This VPB-predominant phenotype was not seen with 1 variant that increased late sodium current, or with variants that reduced peak current density or had mixed effects. In the latter groups, affected individuals mainly showed sinus node dysfunction, conduction defects, and atrial arrhythmias, with infrequent VPB and ventricular arrhythmias. DCM did not occur in the absence of arrhythmias for any variant. Twelve studies (23 total patients) reported treatment success in the VPB-predominant cardiomyopathy using sodium channel-blocking drug therapy. CONCLUSIONS: SCN5A variants can present with a diverse spectrum of primary arrhythmic features. A majority of DCM-associated variants cause a multifocal VPB-predominant cardiomyopathy that is reversible with sodium channel blocking drug therapy. Early recognition of the distinctive phenotype and prompt genetic testing to identify variant carriers are needed. Our findings have implications for interpretation and management of SCN5A variants found in DCM patients with and without arrhythmias.

C/EBPB-dependent adaptation to palmitic acid promotes tumor formation in hormone receptor negative breast cancer.

Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer. Moreover, it is known that obesity promotes stem cell-like properties of breast cancer cells. However, the cancer cell-autonomous mechanisms underlying this correlation are not well defined. Here we demonstrate that obesity-associated tumor formation is driven by cellular adaptation rather than expansion of pre-existing clones within the cancer cell population. While there is no correlation with specific mutations, cellular adaptation to obesity is governed by palmitic acid (PA) and leads to enhanced tumor formation capacity of breast cancer cells. This process is governed epigenetically through increased chromatin occupancy of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPB). Obesity-induced epigenetic activation of C/EBPB regulates cancer stem-like properties by modulating the expression of key downstream regulators including CLDN1 and LCN2. Collectively, our findings demonstrate that obesity drives cellular adaptation to PA drives tumor initiation in the obese setting through activation of a C/EBPB dependent transcriptional network.

Contemporary and Future Approaches to Precision Medicine in Inherited Cardiomyopathies: JACC Focus Seminar 3/5.

Inherited cardiomyopathies are commonly occurring myocardial disorders that are associated with substantial morbidity and mortality. Clinical management strategies have focused on treatment of heart failure and arrhythmic complications in symptomatic patients according to standardized guidelines. Clinicians are now being urged to implement precision medicine, but what does this involve? Advances in understanding of the genetic underpinnings of inherited cardiomyopathies have brought new possibilities for interventions that are tailored to genes, specific variants, or downstream mechanisms. However, the phenotypic variability that can occur with any given pathogenic variant suggests that factors other than single driver gene mutations are often involved. This is propelling a new imperative to elucidate the nuanced ways in which individual combinations of genetic variation, comorbidities, and lifestyle may influence cardiomyopathy phenotypes. Here, Part 3 of a 5-part precision medicine Focus Seminar series reviews the current status and future opportunities for precision medicine in the inherited cardiomyopathies.

Decoding cancer's camouflage: epithelial-mesenchymal plasticity in resistance to immune checkpoint blockade.

Epithelial-mesenchymal plasticity (EMP) of cancer cells contributes to cancer cell heterogeneity, and it is well established that EMP is a critical determinant of acquired resistance to cancer treatment modalities including radiation therapy, chemotherapy, and targeted therapies. Here, we aimed to explore how EMP contributes to cancer cell camouflage, allowing an ever-changing population of cancer cells to pass under the radar of our immune system and consequently compromise the effect of immune checkpoint blockade therapies. The ultimate clinical benefit of any combination regimen is evidenced by the sum of the drug-induced alterations observed in the variety of cellular populations composing the tumor immune microenvironment. The finely-tuned molecular crosstalk between cancer and immune cells remains to be fully elucidated, particularly for the spectrum of malignant cells along the epithelial to mesenchymal axis. High-dimensional single cell analyses of specimens collected in ongoing clinical studies is becoming a key contributor to our understanding of these interactions. This review will explore to what extent targeting EMP in combination with immune checkpoint inhibition represents a promising therapeutic avenue within the overarching strategy to reactivate a halting cancer-immunity cycle and establish a robust host immune response against cancer cells. Therapeutic strategies currently in clinical development will be discussed.

AXL Is a Driver of Stemness in Normal Mammary Gland and Breast Cancer.

The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl + cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when co-opted, maintains acquired stemness in breast cancer cells.