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.

Preoperative ß-Blockade with Propranolol Reduces Biomarkers of Metastasis in Breast Cancer: A Phase II Randomized Trial.

PURPOSE: The majority of deaths from breast cancer occur following the development of metastatic disease, a process inhibited by ß-blockers in preclinical studies. This phase II randomized controlled trial evaluated the effect of preoperative ß-blockade with propranolol on biomarkers of metastatic potential and the immune cell profile within the primary tumor of patients with breast cancer. PATIENTS AND METHODS: In this triple-blind placebo-controlled clinical trial, 60 patients were randomly assigned to receive an escalating dose of oral propranolol (n = 30; 80-160 mg daily) or placebo (n = 30) for 7 days prior to surgery. The primary endpoint investigated the effect of propranolol on prometastatic and proinflammatory gene expression within the primary tumor. RESULTS: Propranolol downregulated primary tumor expression of mesenchymal genes (P = 0.002) without affecting epithelial gene expression (P = 0.21). Bioinformatic analyses implicated downregulation of Snail/Slug (P = 0.03), NF-κB/Rel (P < 0.01), and AP-1 (P < 0.01) transcription factors in structuring the observed transcriptome alterations, and identified changes in intratumoral neutrophil, natural killer cell, and dendritic cell recruitment (all P < 0.01). Patients with clinical evidence of drug response (lowered heart rate and blood pressure) demonstrated elevated tumor infiltration of CD68+ macrophages and CD8+ T cells. CONCLUSIONS: One week of ß-blockade with propranolol reduced intratumoral mesenchymal polarization and promoted immune cell infiltration in early-stage surgically-resectable breast cancer. These results show that ß-blockade reduces biomarkers associated with metastatic potential, and support the need for larger phase III clinical trials powered to detect the impact of ß-blockade on cancer recurrence and survival.See related commentary by Blaes et al., p. 1781.

Publisher Correction: Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis.

In the version of this article originally published, the institution in affiliation 10 was missing. Affiliation 10 was originally listed as Department of Surgery, Royal Melbourne Hospital and Royal Womens' Hospital, Melbourne, Victoria, Australia. It should have been Department of Surgery, Royal Melbourne Hospital and Royal Womens' Hospital, University of Melbourne, Melbourne, Victoria, Australia. The error has been corrected in the HTML and PDF versions of this article.

Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis.

The quantity of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is a robust prognostic factor for improved patient survival, particularly in triple-negative and HER2-overexpressing BC subtypes1. Although T cells are the predominant TIL population2, the relationship between quantitative and qualitative differences in T cell subpopulations and patient prognosis remains unknown. We performed single-cell RNA sequencing (scRNA-seq) of 6,311 T cells isolated from human BCs and show that significant heterogeneity exists in the infiltrating T cell population. We demonstrate that BCs with a high number of TILs contained CD8+ T cells with features of tissue-resident memory T (TRM) cell differentiation and that these CD8+ TRM cells expressed high levels of immune checkpoint molecules and effector proteins. A CD8+ TRM gene signature developed from the scRNA-seq data was significantly associated with improved patient survival in early-stage triple-negative breast cancer (TNBC) and provided better prognostication than CD8 expression alone. Our data suggest that CD8+ TRM cells contribute to BC immunosurveillance and are the key targets of modulation by immune checkpoint inhibition. Further understanding of the development, maintenance and regulation of TRM cells will be crucial for successful immunotherapeutic development in BC.

Mythical 'Tails of Lockwood'.

The cause of testicular ectopia has long been a mystery, and over the years, many hypotheses have been suggested to explain the condition. The most famous of these hypotheses is that of the 'Tails of Lockwood'. This developed from a paper written in 1888 by Charles Barrett Lockwood. Although little evidence has ever been found to corroborate this hypothesis, it remains in many textbooks and journal articles to the present day. In the 21st century, this theory should no longer be given as the cause for ectopic testes. Current biological evidence supports a complex process of growth, by elongation and migration of the gubernaculum, rather than a simple mechanical process of testicular descent, as proposed in the 18th century.

The migrating gubernaculum grows like a "limb bud".

BACKGROUND: The gubernaculum is crucial for testicular descent, and in the second, or inguinoscrotal, phase of descent it has no caudal attachments. Cranially, it is attached to the testis, but its caudal free tip migrates to the scrotum controlled by the genitofemoral nerve. Recent studies show active proliferation in the tip. We hypothesized that the gubernacular tip may grow like a limb bud. METHODS: We performed whole-mount in situ hybridization studies on male and female fetal mice (ages, E14.5-E18.5; n = 162) looking for limb bud regulatory factors. RESULTS: Our results showed that a member of the fibroblast growth factor (Fgf) family, Fgf10, and Hoxa10 were both expressed in the male gubernaculum at E14.5, and Hoxa10 was also expressed in the E16.5 mice. Weak staining was seen in the female gubernaculum for Hoxa10 on days E14.5 and E16.5, whereas no staining for Fgf10 was seen in the female gubernaculums. CONCLUSIONS: These studies, although preliminary, suggest limb bud regulators are essential for gubernacular growth. Hox genes and Fgfs may be fruitful areas of research to unravel the molecular control of gubernacular migration during testicular descent.