Background Statins are hypothesized to reduce the risk of cardiotoxicity associated with anthracyclines and trastuzumab. Our aim was to study the association of statin exposure with hospitalization or emergency department visits (hospital presentations) for heart failure (HF) after anthracycline‐ and/or trastuzumab‐containing chemotherapy for early breast cancer. Methods and Results Using linked administrative databases, we conducted a retrospective cohort study of women aged ≥66 years without prior HF who received anthracyclines or trastuzumab for newly diagnosed early breast cancer in Ontario between 2007 to 2017. Statin‐exposed and unexposed women were matched 1:1 using propensity scores. Trastuzumab‐treated women were also matched on anthracycline exposure. We matched 666 statin‐discordant pairs of anthracycline‐treated women and 390 pairs of trastuzumab‐treated women (median age, 69 and 71 years, respectively). The 5‐year cumulative incidence of HF hospital presentations after anthracyclines was 1.2% (95% CI, 0.5%–2.6%) in statin‐exposed women and 2.9% (95% CI, 1.7%–4.6%) in unexposed women ( P value, 0.01). The cause‐specific hazard ratio associated with statins in the anthracycline cohort was 0.45 (95% CI, 0.24–0.85; P value, 0.01). After trastuzumab, the 5‐year cumulative incidence of HF hospital presentations was 2.7% (95% CI, 1.2%–5.2%) in statin‐exposed women and 3.7% (95% CI, 2.0%–6.2%) in unexposed women ( P value 0.09). The cause‐specific hazard ratio associated with statins in the trastuzumab cohort was 0.46 (95% CI, 0.20–1.07; P value, 0.07). Conclusions Statin‐exposed women had a lower risk of HF hospital presentations after early breast cancer chemotherapy involving anthracyclines, with non‐significant trends towards lower risk following trastuzumab. These findings support the development of randomized controlled trials of statins for prevention of cardiotoxicity.

Glioblastoma (GBM) carries a dismal prognosis and inevitably relapses despite aggressive therapy. Many members of the Eph receptor tyrosine kinase (EphR) family are expressed by GBM stem cells (GSC), which have been implicated in resistance to GBM therapy. In this study, we identify several EphRs that mark a therapeutically targetable GSC population in treatment-refractory, recurrent GBM (rGBM). Using a highly specific EphR antibody panel and CyTOF (cytometry by time-of-flight), we characterized the expression of all 14 EphR in primary and recurrent patient-derived GSCs to identify putative rGBM-specific EphR. EPHA2 and EPHA3 coexpression marked a highly tumorigenic cell population in rGBM that was enriched in GSC marker expression. Knockdown of EPHA2 and EPHA3 together led to increased expression of differentiation marker GFAP and blocked clonogenic and tumorigenic potential, promoting significantly higher survival Treatment of rGBM with a bispecific antibody against EPHA2/A3 reduced clonogenicity and tumorigenic potential of xenografted recurrent GBM via downregulation of AKT and ERK and increased cellular differentiation. In conclusion, we show that EPHA2 and EPHA3 together mark a GSC population in rGBM and that strategic cotargeting of EPHA2 and EPHA3 presents a novel and rational therapeutic approach for rGBM. Treatment of rGBM with a novel bispecific antibody against EPHA2 and EPHA3 reduces tumor burden, paving the way for the development of therapeutic approaches against biologically relevant targets in rGBM. .

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