Mammographic Density and the Risk and Detection of Breast Cancer

Norman F. Boyd, M.D., D.Sc., Helen Guo, M.Sc., Lisa J. Martin, Ph.D., Limei Sun, M.Sc., Jennifer Stone, M.Sc., Eve Fishell, M.D., F.R.C.P.C., Roberta A. Jong, M.D., F.R.C.P.C., Greg Hislop, M.D., F.R.C.P.C., Anna Chiarelli, Ph.D., Salomon Minkin, Ph.D., and Martin J. Yaffe, Ph.D.

ABSTRACT
Background Extensive mammographic density is associated with an increased risk of breast cancer and makes the detection of cancer by mammography difficult, but the influence of density on risk according to method of cancer detection is unknown.
Methods We carried out three nested case–control studies in screened populations with 1112 matched case–control pairs. We examined the association of the measured percentage of density in the baseline mammogram with risk of breast cancer, according to method of cancer detection, time since the initiation of screening, and age.
Results As compared with women with density in less than 10% of the mammogram, women with density in 75% or more had an increased risk of breast cancer (odds ratio, 4.7; 95% confidence interval [CI], 3.0 to 7.4), whether detected by screening (odds ratio, 3.5; 95% CI, 2.0 to 6.2) or less than 12 months after a negative screening examination (odds ratio, 17.8; 95% CI, 4.8 to 65.9). Increased risk of breast cancer, whether detected by screening or other means, persisted for at least 8 years after study entry and was greater in younger than in older women. For women younger than the median age of 56 years, 26% of all breast cancers and 50% of cancers detected less than 12 months after a negative screening test were attributable to density in 50% or more of the mammogram.
Conclusions Extensive mammographic density is strongly associated with the risk of breast cancer detected by screening or between screening tests. A substantial fraction of breast cancers can be attributed to this risk factor.

http://content.nejm.org/cgi/content/full/356/3/227

Prognostic Significance of, and Gene and MicroRNA Expression Signatures Associated With, CEBPA Mutations in Cytogenetically Normal Acute Myeloid Leuke

Guido Marcucci,* Kati Maharry, Michael D. Radmacher, Krzysztof Mrózek, Tamara Vukosavljevic, Peter Paschka, Susan P. Whitman, Christian Langer, Claudia D. Baldus, Chang-Gong Liu, Amy S. Ruppert, Bayard L. Powell, Andrew J. Carroll, Michael A. Caligiuri, Jonathan E. Kolitz, Richard A. Larson, and Clara D. Bloomfield

From the Division of Hematology and Oncology, Department of Internal Medicine, and Division of Human Cancer Genetics, Department of Microbiology, Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH; The Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham; Wake Forest University School of Medicine, Winston-Salem, NC; University of Alabama at Birmingham, Birmingham, AL; North Shore University Hospital, Manhasset, NY; University of Chicago, Chicago, IL; and Charité University Hospital, Berlin, Germany.
* To whom correspondence should be addressed. E-mail: guido.marcucci@osumc.edu

Purpose: To evaluate the prognostic significance of CEBPA mutations in the context of established molecular markers in cytogenetically normal (CN) acute myeloid leukemia (AML) and gain biologic insights into leukemogenesis of the CN-AML molecular high-risk subset (FLT3 internal tandem duplication [ITD] positive and/or NPM1 wild type) that has a significantly higher incidence of CEBPA mutations than the molecular low-risk subset (FLT3-ITD negative and NPM1 mutated).
Patients and Methods: One hundred seventy-five adults age less than 60 years with untreated primary CN-AML were screened before treatment for CEBPA, FLT3, MLL, WT1, and NPM1 mutations and BAALC and ERG expression levels. Gene and microRNA (miRNA) expression profiles were obtained for the CN-AML molecular high-risk patients.
Results: CEBPA mutations predicted better event-free (P = .007), disease-free (P = .014), and overall survival (P < .001) independently of other molecular and clinical prognosticators. Among patients with CEBPA mutations, 91% were in the CN-AML molecular high-risk group. Within this group, CEBPA mutations predicted better event-free (P < .001), disease-free (P = .004), and overall survival (P = .009) independently of other molecular and clinical characteristics and were associated with unique gene and miRNA expression profiles. The major features of these profiles were upregulation of genes (eg, GATA1, ZFPM1, EPOR, and GFI1B) and miRNAs (ie, the miR-181 family) involved in erythroid differentiation and downregulation of homeobox genes. Conclusion: Pretreatment testing for CEBPA mutations identifies CN-AML patients with different outcomes, particularly in the molecular high-risk group, thus improving molecular risk-based classification of this large cytogenetic subset of AML. The gene and miRNA expression profiling provided insights into leukemogenesis of the CN-AML molecular high-risk group, indicating that CEBPA mutations are associated with partial erythroid differentiation.

http://jco.ascopubs.org/cgi/content/short/JCO.2008.17.5554v1?rss=1