The use of the Gail model, body mass index and SNPs to predict breast cancer among women with abnormal (BI-RADS 4) mammograms.

INTRODUCTION: Mammography screening results in a significant number of false-positives. The use of pretest breast cancer risk factors to guide follow-up of abnormal mammograms could improve the positive predictive value of screening. We evaluated the use of the Gail model, body mass index (BMI), and genetic markers to predict cancer diagnosis among women with abnormal mammograms. We also examined the extent to which pretest risk factors could reclassify women without cancer below the biopsy threshold. METHODS: We recruited a prospective cohort of women referred for biopsy with abnormal (BI-RADS 4) mammograms according to the American College of Radiology's Breast Imaging-Reporting and Data System (BI-RADS). Breast cancer risk factors were assessed prior to biopsy. A validated panel of 12 single-nucleotide polymorphisms (SNPs) associated with breast cancer were measured. Logistic regression was used to assess the association of Gail risk factors, BMI and SNPs with cancer diagnosis (invasive or ductal carcinoma in situ). Model discrimination was assessed using the area under the receiver operating characteristic curve, and calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. The distribution of predicted probabilities of a cancer diagnosis were compared for women with or without breast cancer. RESULTS: In the multivariate model, age (odds ratio (OR)=1.05; 95% confidence interval (CI), 1.03 to 1.08; P<0.001), SNP panel relative risk (OR=2.30; 95% CI, 1.06 to 4.99, P=0.035) and BMI (≥30 kg/m2 versus <25 kg/m(2); OR=2.20; 95% CI, 1.05 to 4.58; P=0.036) were significantly associated with breast cancer diagnosis. Older women were more likely than younger women to be diagnosed with breast cancer. The SNP panel relative risk remained strongly associated with breast cancer diagnosis after multivariable adjustment. Higher BMI was also strongly associated with increased odds of a breast cancer diagnosis. Obese women (OR=2.20; 95% CI, 1.05 to 4.58; P=0.036) had more than twice the odds of cancer diagnosis compared to women with a BMI<25 kg/m2. The SNP panel appeared to have predictive ability among both white and black women. CONCLUSIONS: Breast cancer risk factors, including BMI and genetic markers, are predictive of cancer diagnosis among women with BI-RADS 4 mammograms. Using pretest risk factors to guide follow-up of abnormal mammograms could reduce the burden of false-positive mammograms.

Incremental impact of breast cancer SNP panel on risk classification in a screening population of white and African American women.

Breast cancer risk prediction remains imperfect, particularly among non-white populations. This study examines the impact of including single-nucleotide polymorphism (SNP) alleles in risk prediction for white and African American women undergoing screening mammogram. Using a prospective cohort study, standard risk information and buccal swabs were collected at the time of screening mammography. A 12 SNP panel was performed by deCODE genetics. Five-year and lifetime risks incorporating SNPs were calculated by multiplying estimated Breast Cancer Risk Assessment Tool (BCRAT) risk by the total genetic risk ratio. Concordance between the BCRAT and the combined model (BCRAT + SNPs) in identifying high-risk women was measured using the kappa statistic. SNP data were available for 810 women (39 % African American, 55 % white). The mean BCRAT 5-year risk was 1.71 % for whites and 1.18 % for African Americans. Mean genetic risk ratios were 1.09 in whites and 1.29 in African Americans. Among whites, three SNPs had higher frequencies, and among African Americans, seven SNPs had higher and four had lower high-risk allele frequencies than previously reported. Agreement between the BCRAT and the combined model was relatively low for identifying high-risk women (5-year κ = 0.54, lifetime κ = 0.36). Addition of SNPs had the greatest effect among African Americans, with 12.4 % identified as having high-5-year risk by BCRAT, but 33 % by the combined model. A greater proportion of African Americans were reclassified as having high-5-year risk than whites using the combined model (21 vs. 10 %). The addition of SNPs to the BCRAT reclassifies the high-risk status of some women undergoing screening mammography, particularly African Americans. Further research is needed to determine the clinical validity and utility of the SNP panel for use in breast cancer risk prediction, particularly among African Americans for whom these risk alleles have generally not been validated.

Clostridium subterminale Septicemia in a Patient with Metastatic Gastrointestinal Adenocarcinoma.

Clostridium subterminale is a rare member of the Clostridiaceae family that is rarely cultured. This report examines a case of Clostridium subterminale cultured from the blood of a 72-year-old man who was ultimately diagnosed with metastatic gastrointestinal (GI) adenocarcinoma. The patient was receiving treatment for nosocomial pneumonia prior to culture of the C. subterminale, which led to suspicion for malignancy. Extensive GI and oncologic workup demonstrated multiple comorbidities and a primary GI cancer, which likely caused a breach in the GI mucosa and C. subterminale entrance into the bloodstream. After a prolonged intensive care unit (ICU) stay, the patient died on hospital day 23. Though rarely reported, C. subterminale septicemia has been demonstrated in patients with malignancy, specifically of the GI tract. Therefore, this case represents a typical C. subterminale septicemia patient. Given the prevalence of Clostridia and the contemporary emergence of multidrug resistant (MDR) microorganisms, both typical and atypical cases regarding rare members of the species have a significant role in the clinical management and public health planning.

PALB2 mutations in familial breast and pancreatic cancer.

PALB2 (Partner And Localizer of BRCA2) binds to and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1-2% of familial breast cancer and 3-4% of familial pancreatic cancer cases. The goal of this study was to evaluate the prevalence of PALB2 mutations in women with breast cancer without BRCA1/2 mutations who also had a personal or family history of pancreatic cancer. PALB2 mutation analysis was performed in 94 non-BRCA1/2 breast cancer patients with a personal or family history of pancreatic cancer. Two truncating PALB2 mutations, c.3549C>CA and c.2962C>CT, were identified resulting in a mutation prevalence of 2.1%. The proband found to carry the c.3549C>CA PALB2 mutation had a mother diagnosed with both breast and pancreatic cancer; this relative was subsequently confirmed to carry the identical mutation. The proband with the c.2962C>CT mutation had a father and paternal aunt diagnosed with pancreatic cancer; neither relative was available for testing. Two novel PALB2 missense variants were also found, one of which was deemed potentially deleterious. The prevalence rate of PALB2 mutations in a non-BRCA1/2 breast cancer population specifically selected for a family history of pancreatic cancer does not appear to be significantly increased compared to that observed in other breast cancer populations studied thus far. Further evaluation is needed to determine the prevalence of PALB2 mutations and the clinical utility of such testing in those individuals affected with both breast and pancreatic cancers.