Statin use and risks of breast cancer recurrence and mortality.

BACKGROUND: Preclinical evidence suggests improved breast cancer survival associated with statin use, but findings from observational studies are conflicting and remain inconclusive. The objective of this study was to assess the association between statin use after cancer diagnosis and cancer outcomes among breast cancer patients. METHODS: In this retrospective cohort study, 38,858 women aged ≥66 years who were diagnosed with localized and regional stage breast cancer from 2008 through 2017 were identified from the linked Surveillance, Epidemiology, and End Results Medicare database. Statin use was ascertained from Medicare Part D pharmacy claims data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnosis statin use and risks of breast cancer recurrence and breast cancer-specific mortality. RESULTS: Over a median follow-up of 2.9 years for recurrence and 3.7 years for mortality, 1446 women experienced a recurrence, and 2215 died from breast cancer. The mean duration of post-diagnosis statin use was 2.2 years. Statin use post-diagnosis was not associated with recurrence risk (HR, 1.05; 95% CI, 0.91-1.21), but was associated with a reduced risk of cancer-specific mortality (HR, 0.85; 95% CI, 0.75-0.96). The reduction was more pronounced in women with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (HR, 0.71; 95% CI, 0.57-0.88). CONCLUSIONS: These findings suggest that post-diagnosis statin use is associated with improved cancer-specific survival in women with breast cancer and should be confirmed in randomized trials of statin therapy in breast cancer patients.

The role of the PIK3CA gene in the development and aging of the brain.

The CLOVES syndrome is an overgrowth disease arising from mosaic activating somatic mutations in the PIK3CA gene. These mutations occur during fetal development producing malformation and overgrowth of a variety of tissues. It has recently been shown that treatment with low doses of a selective inhibitor of Class I PI3K catalytic subunit p110α, the protein product of the PIK3CA gene, can yield dramatic therapeutic benefits for patients with CLOVES and PROS (a spectrum of PIK3CA-related overgrowth syndromes). To assess the long-term effects of moderate loses of p110α activity, we followed development and growth of mice with heterozygous loss of p110α (Pik3ca+/-) over their entire lifetimes, paying particular attention to effects on the brain. While homozygous deletion of the Pik3ca gene is known to result in early embryonic lethality, these Pik3ca+/- mice displayed a longer lifespan compared to their wild-type littermates. These mice appeared normal, exhibited no obvious behavioral abnormalities, and no body weight changes. However, their brains showed a significant reduction in size and weight. Notably, mice featuring deletion of one allele of Pik3ca only in the brain also showed gradually reduced brain size and weight. Mechanistically, either deletion of p110α or pharmacological inhibition of p110α activity reduced neurosphere size, but not numbers, in vitro, suggesting that p110α activity is critical for neuronal stem cells. The phenotypes observed in our two genetically engineered mouse models suggest that the sustained pharmacological inhibition of the PIK3CA activity in human patients might have both beneficial and harmful effects, and future treatments may need to be deployed in a way to avoid or minimize adverse effects.

Association of birth defects with the mode of assisted reproductive technology in a Chinese data-linkage cohort.

OBJECTIVE: To evaluate the impact of assisted reproductive technology (ART) on the offspring of Chinese population. DESIGN: Retrospective, data-linkage cohort. SETTING: Not applicable. PATIENT(S): Live births resulting from ART or natural conception. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Birth defects coded according to ICD-10. RESULT(S): Births after ART were more likely to be female and multiple births, especially after intracytoplasmic sperm injection (ICSI). ART was associated with a significantly increased risk of birth defects, especially, among singleton births, a significantly increased risk in fresh-embryo cycles after in vitro fertilization (IVF) and frozen-embryo cycles after ICSI. Associations between ART and multiple defects, between ART and gastrointestinal malformation, genital organs malformation, and musculoskeletal malformation among singleton births, and between ART and cardiac septa malformation among multiple births were observed. CONCLUSION(S): This study suggests that ART increases the risk of birth defects. Subgroup analyses indicate higher risk for both fresh and frozen embryos, although nonsignificantly for frozen embryos after IVF and for fresh embryos were presented with low power. Larger sample size research is needed to clarify effects from fresh- or frozen-embryo cycles after IVF and ICSI.

Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases.

Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.