IMPORTANCE Over ⅔ of U.S. women are overweight or obese, placing them at increased risk for postmenopausal breast cancer. OBJECTIVE To investigate the associations of overweight and obesity with risk of postmenopausal invasive breast cancer after extended follow-up in the Women’s Health Initiative (WHI) Clinical Trial. DESIGN The WHI protocol incorporated measured height and weight, baseline and annual or biennial mammography, and adjudicated breast cancer endpoints. SETTING 40 U.S. clinical centers. PARTICIPANTS n=67,142 postmenopausal women aged 50–79 years were enrolled from 1993–1998 with a median of 13 years of follow-up through 2010; 3388 invasive breast cancers were observed. MAIN OUTCOMES AND MEASURES Height and weight were measured at baseline and weight was measured annually thereafter. Data were collected on demographic characteristics, personal and family medical history and personal habits (smoking, physical activity). Women underwent annual or biennial mammograms. Breast cancers were verified by medical records reviewed by physician adjudicators. RESULTS Women who were overweight and obese had an increased invasive breast cancer risk vs. normal weight women. Risk was greatest for obesity grades 2+3 (BMI>35.0 kg/m2) (hazard ratio [HR] for invasive breast cancer =1.58, 95% CI 1.40–1.79). BMI ≥ 35.0 kg/m2 was strongly associated with risk for ER+/PR+ breast cancers (HR=1.86 95% CI 1.60–2.17), but was not associated with ER− cancers. Obesity grade 2+3 was also associated with advanced disease including larger tumor size (HR=2.12 95%CI 1.67–2.69). (P=0.02), positive lymph nodes (HR=1.89 95%CI 1.46–2.45), (P=0.06), regional/distant stage (HR=1.94, 95%CI 1.52–2.47) (P=0.05) and deaths after breast cancer (HR=2.11 95%CI 1.57–2.84) (P<0.001). Women with baseline BMI<25.0 kg/m2 who gained >5% of bodyweight over the follow-up period had an increased breast cancer risk (HR=1.36 95% CI 1.1–1.65), but among women already overweight or obese we found no association of weight change (gain or loss) with breast cancer during follow-up. There was no effect modification of the BMI-breast cancer relationship by postmenopausal hormone therapy (HT) and the direction of association across BMI categories was similar for never, past and current HT use. CONCLUSIONS/RELEVANCE Obesity is associated with increased invasive breast cancer risk in postmenopausal women. These clinically meaningful findings should motivate programs for obesity prevention.

Somatic mutations in exon 2 of the RNA polymerase II transcriptional Mediator subunit occur at high frequency in uterine fibroids (UFs) and breast fibroepithelial tumors as well as recurrently, albeit less frequently, in malignant uterine leimyosarcomas, chronic lymphocytic leukemias, and colorectal cancers. Previously, we reported that UF-linked mutations in MED12 disrupt its ability to activate cyclin C (CycC)-dependent kinase 8 (CDK8) in Mediator, implicating impaired Mediator-associated CDK8 activity in the molecular pathogenesis of these clinically significant lesions. Notably, the CDK8 paralog CDK19 is also expressed in myometrium, and both CDK8 and CDK19 assemble into Mediator in a mutually exclusive manner, suggesting that CDK19 activity may also be germane to the pathogenesis of mutation-induced UFs. However, whether and how UF-linked mutations in MED12 affect CDK19 activation is unknown. Herein, we show that MED12 allosterically activates CDK19 and that UF-linked exon 2 mutations in MED12 disrupt its CDK19 stimulatory activity. Furthermore, we find that within the Mediator kinase module, MED13 directly binds to the MED12 C terminus, thereby suppressing an apparent UF mutation-induced conformational change in MED12 that otherwise disrupts its association with CycC-CDK8/19. Thus, in the presence of MED13, mutant MED12 can bind, but cannot activate, CycC-CDK8/19. These findings indicate that MED12 binding is necessary but not sufficient for CycC-CDK8/19 activation and reveal an additional step in the MED12-dependent activation process, one critically dependent on MED12 residues altered by UF-linked exon 2 mutations. These findings confirm that UF-linked mutations in MED12 disrupt composite Mediator-associated kinase activity and identify CDK8/19 as prospective therapeutic targets in UFs.

Fertility preservation counseling is being performed by pediatric oncology providers. Familiarity of the ASCO guidelines is limited, revealing that the established methods for fertility preservation in women--embryo and oocyte cryopreservation--may be offered less than experimental methods in this younger patient population. Such differences in apparent practice patterns highlight the need for more education for providers.

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Objective To assess the effect of assisted hatching (AH) on live birth rates in a retrospective cohort of patients undergoing first-cycle, autologous frozen embryo transfer (FETs). Design Longitudinal cohort using cycles reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System between 2004 and 2013. Setting Not applicable. Patient(s) Women who underwent first cycle, autologous, FETs with (n=70,738) and without (n=80,795) AH reported from 2004 to 2013. Propensity matching was used to account for confounding covariates and a logistic regression model was constructed to identify the predictors of live birth rates in relationship to AH. Interventions Not applicable. Main Outcome Measure Live births. Results In all first-cycle FETs, there was a slight, but statistically significant decrease in live birth rate with AH compared to no AH (34.2% v 35.4%). AH was associated with decreased live births in older patients and in years 2012–2013. Live birth rates and number of AH cycles performed prior to FETs varies by geographical clinic location. Conclusions AH slightly decreases live birth rates in first cycle, autologous FETs. Its use should be carefully considered especially in patients 38 years old and above. Prospective, clinical studies are needed to improve our knowledge of the impact of AH.