Howlader et al. Page 619

This study by Howlader and colleagues presents breast cancer–specific survival by molecular subtypes and important clinical and demographic features using national-level data. Survival patterns were described based on estrogen receptor, progesterone receptor, and HER2 status for cases diagnosed between 2010 and 2013 with up to 4 years of follow-up. Multiple imputation was used to fill in missing information. Stage was the most powerful predictor of survival; within each stage, hormone receptor positive tumors were associated with better survival. Contrary to conventional thought, hormone receptor–positive/HER2-positive subtype (tumors expressing all therapeutic targets) experienced better survival than hormone receptor–positive/HER2-negative in advanced stage disease.

Tang et al. Page 627

Metformin is the first-line drug for type 2 diabetes. Observational studies consistently indicated that metformin is associated with decreased of cancer incidence and mortality. However, many studies describing this association were affected by time-related biases. In the present systematic review and meta-analysis, Tang and colleagues identified a significant protective effect of metformin for all-cause mortality in breast cancer patients with diabetes taking into account study quality and time-related biases. This is the first systematic review and meta-analysis in the field of metformin and breast cancer that used the Grading of Recommendation of Assessment, Development, and Evaluation (GRADE) to assess overall study quality.

Ugge et al. Page 660

Appendicitis before age 20 has been observed to influence the risk of several inflammatory conditions and has been suggested to signal certain immune characteristics. Chronic inflammation has further been implied in the development of prostate cancer. In this large population-based cohort study, Ugge and colleagues found that young men diagnosed with appendicitis are at increased risk of prostate cancer later in life. The authors propose that immunological characteristics signaled by early appendicitis might influence the development of prostatic inflammation and prostate cancer. Evaluating associations between inflammatory conditions and prostate cancer may add to the understanding of inflammatory pathways involved in prostate cancer.

Jordahl et al. Page 689

At diagnosis, bladder cancer tends to be more advanced and of worse prognosis in women than in men. Differential DNA methylation, as measured in blood, may be a useful screening indicator of susceptibility to aid in early diagnosis of bladder cancer. Using resources from the Women's Health Initiative, Jordahl and colleagues conducted the first study of prediagnostic genome-wide DNA methylation and bladder cancer risk and found differential methylation at a locus in CITED4 to be associated with future bladder cancer risk. In addition to confirmation by other prospective studies, molecular studies are needed to determine the role of CITED4 in bladder carcinogenesis.