Ryan D. Frank

Model for Individualized Prediction of Breast Cancer Risk After a Benign Breast Biopsy

PURPOSE Optimal early detection and prevention for breast cancer depend on accurate identification of women at increased risk. We present a risk prediction model that incorporates histologic features of biopsy tissues from women with benign breast disease (BBD) and compare its performance to the Breast Cancer Risk Assessment Tool (BCRAT). METHODS We estimated the age-specific incidence of breast cancer and death from the Mayo BBD cohort and then combined these estimates with a relative risk model derived from 377 patient cases with breast cancer and 734 matched controls sampled from the Mayo BBD cohort to develop the BBD-to-breast cancer (BBD-BC) risk assessment tool. We validated the model using an independent set of 378 patient cases with breast cancer and 728 matched controls from the Mayo BBD cohort and compared the risk predictions from our model with those from the BCRAT. RESULTS The BBD-BC model predicts the probability of breast cancer in women with BBD using tissue-based and other risk factors. The concordance statistic from the BBD-BC model was 0.665 in the model development series and 0.629 in the validation series; these values were higher than those from the BCRAT (0.567 and 0.472, respectively). The BCRAT significantly underpredicted breast cancer risk after benign biopsy (P = .004), whereas the BBD-BC predictions were appropriately calibrated to observed cancers (P = .247). CONCLUSION We developed a model using both demographic and histologic features to predict breast cancer risk in women with BBD. Our model more accurately classifies a womans breast cancer risk after a benign biopsy than the BCRAT.

Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women

Women with atypical hyperplasia (AH) on breast biopsy have a substantially increased risk of breast cancer (BC). Here the BC risk for the extent and subtype of AH is reported for 2 separate cohorts.

Fatty acids found in dairy, protein and unsaturated fatty acids are associated with risk of pancreatic cancer in a case–control study

Although many studies have investigated meat and total fat in relation to pancreatic cancer risk, few have investigated dairy, fish and specific fatty acids (FAs). We evaluated the association between intake of meat, fish, dairy, specific FAs and related nutrients and pancreatic cancer. In our American‐based Mayo Clinic case–control study 384 cases and 983 controls frequency matched on recruitment age, race, sex and residence area (Minnesota, Wisconsin or Iowa, USA) between 2004 and 2009. All subjects provided demographic information and completed 144‐item food frequency questionnaire. Logistic regression‐calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) were adjusted for age, sex, cigarette smoking, body mass index and diabetes mellitus. Significant inverse association (trend p‐value < 0.05) between pancreatic cancer and the groupings (highest vs. lowest consumption quintile OR [95% CI]) was as follows: meat replacement (0.67 [0.43–1.02]), total protein (0.58 [0.39–0.86]), vitamin B12 (0.67 [0.44, 1.01]), zinc (0.48 [0.32, 0.71]), phosphorus (0.62 [0.41, 0.93]), vitamin E (0.51 [0.33, 0.78]), polyunsaturated FAs (0.64 [0.42, 0.98]) and linoleic acid (FA 18:2) (0.62 [0.40–0.95]). Increased risk associations were observed for saturated FAs (1.48 [0.97–2.23]), butyric acid (FA 4:0) (1.77 [1.19–2.64]), caproic acid (FA 6:0) (2.15 [1.42–3.27]), caprylic acid (FA 8:0) (1.87 [1.27–2.76]) and capric acid (FA 10:0) (1.83 [1.23–2.74]). Our study suggests that eating a diet high in total protein and certain unsaturated FAs is associated with decreased risk of developing pancreatic cancer in a dose‐dependent manner, whereas fats found in dairy increase risk.

Clinicopathologic features of breast cancers that develop in women with previous benign breast disease

Women with benign breast disease (BBD) have an increased risk of developing breast cancer (BC). Nearly 30% of all BCs develop in women with prior BBD. Information regarding features of the expected number of BCs after BBD would enhance individualized surveillance and prevention strategies for these women. In the current study, the authors sought to characterize BCs developing in a large cohort of women with BBD.

Mucocele-like lesions of the breast: A clinical outcome and histologic analysis of 102 cases

Mucocele-like lesions (MLLs) of the breast are characterized by cystic architecture with stromal mucin and frequent atypia, but it is unknown whether they convey long-term breast cancer risk. We evaluated 102 MLLs that were derived from a single-institution benign breast disease cohort of 13412 women who underwent biopsy from 1967 to 2001. MLLs were histologically characterized by type of lining epithelium, architecture of the lesion, associated atypical hyperplasia (AH), and incidence of breast cancer (14.8-year median follow-up). A relatively large proportion of MLLs (42%) were diagnosed in women older than 55 years. AH was significantly more frequent in MLL patient compared to the cohort overall (27% versus 5%; P < .001). Breast cancer has developed in 13 patients with MLL. This frequency is only slightly higher than population expected rates overall (standardized incidence ratio, 2.28; 95% confidence interval, 1.21-3.91) and not significantly different from women in the cohort with (nonatypical) proliferative breast lesions. Younger women (<45) with MLL had a nonsignificant increase in risk of cancer compared to the general population (standardized incidence ratio, 5.16; 95% confidence interval, 1.41-13.23). We conclude that MLL is an uncommon breast lesion that is often associated with coexisting AH. However, in women older than 45 years, MLLs do not convey additional risk of breast cancer beyond that associated with the presence of proliferative disease.

Impact of diabetes mellitus on clinical outcomes in patients undergoing surgical resection for pancreatic cancer: a retrospective, cohort study

OBJECTIVES:Diabetes mellitus (DM) has a bidirectional association with pancreatic cancer (PaC); however, its effect on clinical outcomes has not been thoroughly evaluated. We analyzed these data in a large sample of PaC subjects who had undergone surgical resection.METHODS:Subjects enrolled in the Mayo Clinic Pancreatic Cancer SPORE registry from 2000 to 2010 who had resection with curative intent were identified (n=488). Tumor size, cancer stage, and postoperative median survival were evaluated. Median survivals were compared with Kaplan–Meier curves and Cox proportional hazards regression modeling.RESULTS:A total of 275 (56%) subjects had DM before surgery. DM subjects had larger tumors compared with those without DM (3.6 cm vs. 3.3, P=0.002), even after controlling for covariates including age, body mass index, and tumor grade. Cancer stage at the time of surgery was not affected by DM status (P=0.575). Preoperative DM was not associated with an increased risk of death using a multivariable survival analysis (hazard ratio 1.06, 95% confidence interval 0.81–1.38, P=0.676). The median survival following cancer resection was similar between subjects with and without DM (24 vs. 26 months, P=0.610). In addition, postoperative survival was similar on the basis of the duration of DM (new-onset vs. long-standing) and prior use of antidiabetic treatments in diabetic subjects.CONCLUSIONS:PaC subjects with DM have larger tumors than nondiabetic subjects. Despite this observation, preoperative DM does not negatively impact the cancer stage at the time of surgery or postoperative survival. Thus, the effect of DM on tumor size is either overshadowed by early metastatic spread of the cancer or is mitigated by the tumor resection.

Randomized Clinical Trial of a Combination of an Inhaled Corticosteroid and Beta Agonist in Patients at Risk of Developing the Acute Respiratory Distress Syndrome.

Objectives: Effective pharmacologic treatments directly targeting lung injury in patients with the acute respiratory distress syndrome are lacking. Early treatment with inhaled corticosteroids and beta agonists may reduce progression to acute respiratory distress syndrome by reducing lung inflammation and enhancing alveolar fluid clearance. Design: Double-blind, randomized clinical trial (ClinicalTrials.gov: NCT01783821). The primary outcome was longitudinal change in oxygen saturation divided by the FIO2 (S/F) through day 5. We also analyzed categorical change in S/F by greater than 20%. Other outcomes included need for mechanical ventilation and development of acute respiratory distress syndrome. Setting: Five academic centers in the United States. Patients: Adult patients admitted through the emergency department at risk for acute respiratory distress syndrome. Interventions: Aerosolized budesonide/formoterol versus placebo bid for up to 5 days. Measurements and Main Results: Sixty-one patients were enrolled from September 3, 2013, to June 9, 2015. Median time from presentation to first study drug was less than 9 hours. More patients in the control group had shock at enrollment (14 vs 3 patients). The longitudinal increase in S/F was greater in the treatment group (p = 0.02) and independent of shock (p = 0.04). Categorical change in S/F improved (p = 0.01) but not after adjustment for shock (p = 0.15). More patients in the placebo group developed acute respiratory distress syndrome (7 vs 0) and required mechanical ventilation (53% vs 21%). Conclusions: Early treatment with inhaled budesonide/formoterol in patients at risk for acute respiratory distress syndrome is feasible and improved oxygenation as assessed by S/F. These results support further study to test the efficacy of inhaled corticosteroids and beta agonists for prevention of acute respiratory distress syndrome.

Meat-Related Mutagens and Pancreatic Cancer: Null Results from a Clinic-Based Case–Control Study

Background: Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. The study objective was to evaluate risk of pancreatic cancer associated with meat preparation methods and meat-related mutagen consumption using a clinic-based case–control design. Methods: There were 384 cases and 983 controls; subjects provided demographic information and completed a 144-item food frequency questionnaire, which was used to estimate meat mutagen intake using the National Cancer Institutes CHARRED database (Bethesda, MD). Logistic regression was used to calculate ORs and 95% confidence intervals (CI), adjusted for factors including age, sex, cigarette smoking, body mass index, and diabetes mellitus. Results: Overall, the findings were null with respect to meat mutagen intake and pancreatic cancer. Conclusions: The results do not support an association between well-done meat or meat-related mutagen intake and pancreatic cancer and contrast with generally increased risks reported in previous studies. Impact: These data contribute to evidence about pancreatic cancer and potentially carcinogenic compounds in meat. Cancer Epidemiol Biomarkers Prev; 22(7); 1336–9. ©2013 AACR.

Second primary acute lymphoblastic leukemia in adults: a SEER analysis of incidence and outcomes

We conducted a surveillance epidemiology and end results (SEER)‐based analysis to describe the incidence and characteristics of second primary acute lymphoblastic leukemia (sALL) among adults (≥18 years) with a history of primary malignancies (1M). Standardized incidence ratios (SIRs) of sALL cases were calculated by site and 1M stage. We also evaluated the differences in 5‐year sALL survival by age, site, and extent of 1M, latency of sALL after 1M, and evidence of underlying racial/ethnic disparity. We identified 10,956 patients with de‐novo/primary acute lymphoblastic leukemia (1ALL) and 772 with sALL. Women (49.1% vs. 42.9%), white patients (72.0% vs. 59.5%), older patients (58.8% vs. 25.2%; age ≥65 years), and patients diagnosed between 2003 and 2012 (66.8% vs. 53.9%) had a higher proportion of sALL compared with 1ALL. There was a significantly inferior median 5‐year survival for sALL patients compared to 1ALL (6 vs. 15 months; HR 1.20, 95% CI 1.10–1.31, P < 0.001). The median latency period was 60.0 months; the most common 1M among sALL patients were breast (17.9%) and prostate (17.4%). Patients with any 1M were at increased risk of developing sALL (SIR 1.76, 95% CI 1.58–1.95, P < 0.001). Hematological‐1M sites had significantly higher SIRs (hematological‐SIR 7.35; solid‐SIR 1.33; P < 0.001). We observed a significant increase in sALL incidence after a 1M and a significantly worse 5‐year survival with different demographic characteristics from 1ALL. There is a need to define appropriate screening methods for patients surviving their primary cancer.

Breast Cancer Risk and Progressive Histology in Serial Benign Biopsies

Background: More than 1 million women per year in the United States with benign breast biopsies are known to be at elevated risk for breast cancer (BC), with risk stratified on histologic categories of epithelial proliferation. Here we assessed women who had serial benign biopsies over time and how changes in the histologic classification affected BC risk. Methods: In the Mayo Clinic Benign Breast Disease Cohort of 13 466 women, 1414 women had multiple metachronous benign biopsies (10.5%). Both initial and subsequent biopsies were assessed histologically. BC risk for clinical and prognostic factors was assessed using subdistribution models to account for competing risks, and logistic regression/Wilcoxon/chi-square tests to assess covariates. All statistical tests were two-sided. Results: Breast cancer risk for women with serial biopsies, stratified by histologic category in the later biopsies, was similar to women with a single biopsy. We found that changes in histological category between initial and subsequent biopsy statistically significantly impacted BC risk. Women with nonproliferative initial findings and subsequent proliferative findings had an increased risk (hazard ratio [HR] = 1.77, 95% confidence interval [CI] = 1.06 to 2.94, P = .03) compared with no change. Among women with proliferative disease without atypia at initial biopsy, risk decreased if later biopsy regressed to nonproliferative (HR = 0.49, 95% CI = 0.25 to 0.98) and increased if later biopsy showed progression to atypical hyperplasia (HR = 1.49, 95% CI = 0.73 to 3.05) compared with no change (P = .04). Conclusions: We found that breast cancer risk increases in women with progressive epithelial proliferation over time and decreases in women whose biopsies show less proliferation. This finding has important implications for effective clinical management of the 100 000 women per year who have multiple benign breast biopsies.