Citations

Abstract Multigene panel testing (MGPT) for hereditary cancer is increasing in popularity in the USA. Many panels include genes identified as hereditary breast and/or ovarian cancer (HBOC) genes despite limited data regarding the precise cancer risks associated with mutations in these genes. Here we report on results from BreastNext and OvaNext panel testing of 20 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11A, MSH2, MSH6, NBN, NF1, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, TP53) in a cohort of 15,083 individuals. The majority of individuals were from high-risk breast and/or ovarian (Br/Ov) cancer families, with 92.4% of all probands meeting National Comprehensive Cancer Network HBOC testing criteria. Pathogenic mutations were identified in 9.4% of the overall cohort. To estimate gene-specific breast and ovarian cancer risks, case-control analyses were performed comparing the frequencies of pathogenic mutations from Caucasian breast or ovarian cancer cases from BreastNext and OvaNext with frequencies from Caucasian, non-Finnish, non-TCGA controls from the Exome Aggregation Consortium (ExAC) database. Mutations in the well studied ATM and CHEK2 genes were associated with moderate risks (OR>2) of breast cancer and mutations in PALB2 were associated with high-risks (OR>5) of breast cancer, consistent with previous reports. In addition, the study suggested that pathogenic mutations in MSH6, RAD51D, CDH1, and NF1 are associated with moderate to high risks of breast cancer. In contrast, RAD51C, RAD51D, and BRIP1 mutations were associated with high risks of ovarian cancer, PALB2 mutations were associated with moderate risks, but ATM and CHEK2 mutations were not associated with increased ovarian cancer risk. In addition, modeling of missense mutations in the predisposition genes using in silico prediction algorithms suggested that missense mutations in CDH1, CHEK2, MSH2, and MSH6 are associated with moderate risks of breast cancer and missense mutations in RAD51C increase risks of ovarian cancer. This large breast and ovarian cancer case-control analysis provides useful data for many predisposition genes previously lacking risk estimates, and should prove useful for clinical risk management of patients after clinical panel testing. Citation Format: Fergus J. Couch, David E. Goldgar, Steven N. Hart, Emily Hallberg, Raymond Moore, Huong Meeks, Robert Huether, Holly LaDuca, Elizabeth Chao, Jill Dolinsky. Breast and ovarian cancer risks associated with cancer predisposition gene mutations identified by multigene panel testing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2597.

BACKGROUNDPrevious research has demonstrated that cancer survivors often fail to receive recommended care and also undergo unnecessary care; this reduces care quality and increases costs.METHODSThis phase 2 trial randomized 100 stage 0 to IIIa breast cancer patients who had primary care providers within a large Massachusetts‐based hospital network (with accessible online records) to either coordinated follow‐up care (CC), which entailed a tailored survivorship care plan (SCP) and patient navigator calls every 3 months, or standard care (SC), which did not include an SCP or patient navigation, for 1 year after the completion of their last chemotherapy, surgery, or radiation treatment. The primary endpoint was the frequency of redundant examinations (>1 breast/chest wall examination per patient within any 30‐day period in the absence of a new breast or chest wall complaint) over the year of follow‐up. The total number of non–plastic surgery visits in the year of follow‐up was a secondary endpoint.RESULTSTwo patients (both on CC) were ineligible, and 2 patients (1 per arm) had a recurrence or died during follow‐up; this left 96 for analysis (47 in the CC arm and 49 in the SC arm). Twenty‐two of the 47 CC patients (47%; 95% confidence interval, 32%‐62%) and 19 of the 49 SC patients (39%; 95% confidence interval, 25%‐54%) had 1 or more redundant breast/chest wall examinations during the year. The median number of non–plastic surgery visits was 12 for CC patients and 8 for SC patients.CONCLUSIONSEarly‐stage breast cancer patients visit health care providers very frequently during their first year of follow‐up and often receive unnecessary breast/chest wall examinations. An SCP and patient navigator calls did not reduce this surrogate for redundant care. Cancer 2016;122:3546–3554. © 2016 American Cancer Society

Objective: To determine the optimal environmental conditions for chondrogenic differentiation of human adipose tissue–derived mesenchymal stromal/stem cells (AMSCs). In this investigation we specifically investigate the role of oxygen tension and 3-dimensional (3D) culture systems. Design: Both AMSCs and primary human chondrocytes were cultured for 21 days in chondrogenic media under normoxic (21% oxygen) or hypoxic (2% oxygen) conditions using 2 distinct 3D culture methods (high-density pellets and poly-ε-caprolactone [PCL] scaffolds). Histologic analysis of chondro-pellets and the expression of chondrocyte-related genes as measured by reverse transcriptase quantitative polymerase chain reaction were used to evaluate the efficiency of differentiation. Results: AMSCs are capable of expressing established cartilage markers including COL2A1, ACAN, and DCN when grown in chondrogenic differentiation media as determined by gene expression and histologic analysis of cartilage markers. Expression of several cartilage-related genes was enhanced by low oxygen tension, including ACAN and HAPLN1. The pellet culture environment also promoted the expression of hypoxia-inducible cartilage markers compared with cells grown on 3D scaffolds. Conclusions: Cell type–specific effects of low oxygen and 3D environments indicate that mesenchymal cell fate and differentiation potential is remarkably sensitive to oxygen. Genetic programming of AMSCs to a chondrocytic phenotype is effective under hypoxic conditions as evidenced by increased expression of cartilage-related biomarkers and biosynthesis of a glycosaminoglycan-positive matrix. Lower local oxygen levels within cartilage pellets may be a significant driver of chondrogenic differentiation.

Key Points A total of 38% of patients who achieved CR (13 of 34) on brentuximab vedotin have remained in remission for >5 years and may be cured. Nine of the 13 patients (9% of all enrolled patients) have remained in long-term remission without a consolidative allogeneic transplant.

Abstract Background: Despite a large body of literature evaluating the association between recreational physical activity and epithelial ovarian cancer (EOC) risk, the extant evidence is inconclusive, and little is known about the independent association between recreational physical inactivity and EOC risk. We conducted a pooled analysis of nine studies from the Ovarian Cancer Association Consortium to investigate the association between chronic recreational physical inactivity and EOC risk. Methods: In accordance with the 2008 Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. Multivariable logistic regression was utilized to estimate the ORs and 95% confidence intervals (CI) for the association between inactivity and EOC risk overall and by subgroups based upon histotype, menopausal status, race, and body mass index. Results: The current analysis included data from 8,309 EOC patients and 12,612 controls. We observed a significant positive association between inactivity and EOC risk (OR = 1.34; 95% CI, 1.14–1.57), and similar associations were observed for each histotype. Conclusions: In this large pooled analysis examining the association between recreational physical inactivity and EOC risk, we observed consistent evidence of an association between chronic inactivity and all EOC histotypes. Impact: These data add to the growing body of evidence suggesting that inactivity is an independent risk factor for cancer. If the apparent association between inactivity and EOC risk is substantiated, additional work via targeted interventions should be pursued to characterize the dose of activity required to mitigate the risk of this highly fatal disease. Cancer Epidemiol Biomarkers Prev; 25(7); 1114–24. ©2016 AACR.

Background Whereas insurance status has been previously associated with care patterns, little is currently known about the association between Medicaid insurance and the clinical characteristics, treatment, or outcomes of patients with atrial fibrillation ( AF ). Methods and Results We used data from adults with AF enrolled in the Outcomes Registry for Better Informed Treatment of AF ( ORBIT ‐ AF ), a national outpatient registry conducted at 176 community, multispecialty sites. The primary outcome of interest was the proportion of patients prescribed any oral anticoagulation ( OAC ; warfarin or novel oral anticoagulants [ NOAC ]). Secondary outcomes of interest included the proportion of patients prescribed NOAC s (dabigatran or rivaroxaban); time in therapeutic range ( TTR ) for warfarin users, all‐cause mortality, stroke/systemic embolism, and major bleed. Of 10 133 patients, N=470 (4.6%) had Medicaid insurance. Medicaid patients were similarly likely to receive OAC at baseline (72.8% vs 76.3%; unadjusted P =0.079), but less likely to receive NOAC at baseline or follow‐up (12.1% vs 16.3%; unadjusted P =0.019). After risk adjustment, Medicaid status was associated with lower use of OAC at baseline among patients with high stroke risk (odds ratio [ OR ]=0.68; 95% CI =0.49, 0.94), but was not associated with OAC use overall ( OR =0.82; 95% CI =0.61, 1.09). Among warfarin users, median TTR was lower among Medicaid patients (60% vs 68%; P <0.0001; adjusted TTR difference, −2.9; 95% CI =−5.7, −0.2; P =0.04). Use of an NOAC over 2 years of follow‐up was not statistically different by insurance. Compared with non‐Medicaid patients, Medicaid patients had higher unadjusted rates of mortality, stroke/systemic embolism, and major bleeding; however, these differences were attenuated following adjustment for clinical characteristics. Conclusions In a contemporary AF cohort, use of OAC overall and use of NOAC s were not significantly lower among Medicaid patients relative to others. However, among warfarin users, Medicaid patients spent less time in therapeutic range compared with those with other forms of insurance.

Abstract Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.