Frost, Marlene H.

Abstract p16, a nuclear protein encoded by the p16INK4a gene, is a regulator of cell-cycle regulation. Previous studies have shown that expression of p16 in tissue biopsies of patients with ductal carcinoma in situ (DCIS) is associated with increased risk of breast cancer, particularly when considered in combination with other markers such as Ki-67 and COX-2. Here, we evaluated how expression of p16 in breast tissue biopsies of women with atypical hyperplasia (AH), a putative precursor lesion to DCIS, is associated with subsequent development of cancer. p16 expression was assessed by immunohistochemistry in archival sections from 233 women with AH diagnosed at the Mayo Clinic. p16 expression in the atypical lesions was scored by percentage of positive cells and intensity of staining. We also studied coexpression of p16, with Ki-67 and COX-2, biomarkers of progression in AH. Risk factor and follow-up data were obtained via study questionnaire and medical records. Forty-seven patients (20%) developed breast cancer with a median follow-up of 14.5 years. Staining of p16 was increased in older patients relative to younger patients (P = 0.0025). Although risk of developing breast cancer was not associated with increased p16 expression, joint overexpression of Ki-67 and COX-2 was found to convey stronger risk of breast cancer in the first 10 years after diagnosis as compared with one negative marker (P < 0.01). However, the addition of p16 levels did not strengthen this association. p16 overexpression, either alone or in combination with COX-2 and Ki-67, does not significantly stratify breast cancer risk in women with AH. Cancer Prev Res; 4(12); 1953–60. ©2011 AACR.

PURPOSE. The study aims to identify Minnesota nurses' perceptions regarding nursing diagnoses and to examine how these perceptions have changed over time. METHODS. Five hundred sixty-four out of 2,000 randomly selected registered nurses in Minnesota responded to the Perceptions of Nursing Diagnosis Survey. FINDINGS. Nurses have neutral to slightly negative perceptions of nursing diagnoses. These results differ slightly from the results of the original study which demonstrated neutral to slightly positive perceptions. IMPLICATIONS. After 30 years of use, it is concerning that more than half of nurses surveyed have a negative perception of nursing diagnosis. Consideration should be given to methods that facilitate the use of nursing diagnoses in practice, improvement of diagnostic language, or a more accepted method of planning patient care.

Abstract Background: Epithelial proliferation in benign breast disease (BBD) is a well-established biomarker of breast cancer risk, and BBD tissues can be used as a platform to assess other biomarkers for breast cancer risk. Lobular involution (the degree of age-related atrophy in lobules) is a new biomarker, with greater degrees of involution associated with lower breast cancer risk. Successful application of tissue biomarkers of risk to breast tissues from normal women would be valuable for risk prediction in the general population. We hypothesized that normal breast tissue samples would differ from BBD tissues in these histologic features of breast cancer risk, with less epithelial proliferation but a similar degree of involution compared to BBD tissues. Methods: Core biopsy samples from the Mayo Benign Breast Disease Cohort Study were compared to core biopsy samples of normal breast tissue obtained from the Susan G. Komen for the Cure Tissue Bank at IU Simon Cancer Center (KTB), a unique resource of breast tissue from donor women without any known breast abnormalities. All core biopsies were assessed histologically by a single breast pathologist for degree of epithelial proliferation (classified as non-proliferative, proliferative without atypia, or atypical hyperplasia) and extent of lobular involution (classified as none, 1-24%, 25-74%, or >75% of lobules). Data were analyzed using chi-square tests and logistic regression. Results: Overall, 318 Mayo BBD and 303 normal (KTB) core breast biopsy samples were evaluated. As anticipated, significantly less epithelial proliferation was present in normal samples compared to BBD samples. Proliferative disease occurred in 9/303 (3%) of normals versus 79/318 (25%) of BBD, and atypical hyperplasia was seen in 2/303 (0.7%) of normal samples versus 24/318 (8%) of BBD core biopsies, p < 0.0001. This difference remained significant after adjusting for age (which was greater overall in the BBD samples). Complete involution was more frequent in normal compared to BBD tissues, although the difference did not reach statistical significance. The age-adjusted odds ratio of complete involution in normal versus BBD tissues was 1.46 (95% CI 0.98-2.17, p = 0.06), suggesting a possible delay or failure of involution in women with BBD. Conclusions: Histologic features of normal breast tissues are different from those of BBD tissues, with less epithelial proliferation and more lobular involution, consistent with a lower risk of breast cancer expected for women with normal breast tissue compared to those with benign breast disease. Normal breast tissues are a valuable and distinct resource that should be considered for biomarker validation studies. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B23.

Abstract Estrogen receptor (ER) is expressed in normal and malignant breast epithelium, and expression levels have been found to increase with age in normal breast epithelium but not in atypical hyperplasia (AH) and carcinoma in situ. Here we assess ER expression in AH and its association with later breast cancer. ER expression was assessed immunohistochemically in archival sections from 246 women with AH who had open benign breast biopsy from 1967 to 1991. The ACIS III (Dako) was utilized to calculate ER expression in all atypical foci. Using multivariate linear regression, we examined associations of ER expression with age at biopsy, indication for biopsy, type of atypia, number of atypical foci, involution status, and family history. Breast cancer risk across levels of ER expression was also assessed compared with the Iowa SEER control population. Among 246 women, 87 (35%) had atypical ductal hyperplasia (ADH), 141 (57%) had atypical lobular hyperplasia (ALH), and 18 (7%) had both. Forty-nine (20%) developed breast cancer (median follow-up of 14.4 years). Multivariate analysis indicated that type of atypia and age at diagnosis were significantly associated with ER percent staining and intensity (P < 0.05). ER expression was increased in women with ADH and/or those over age 55. ER expression did not significantly impact breast cancer risk in patients diagnosed with atypia. We found increasing ER expression in AH with increasing age. ER expression in AH does not further discriminate breast cancer risk in women with atypia. Cancer Prev Res; 4(3); 435–44. ©2011 AACR.

Abstract Background: p16 is a nuclear protein encoded by the p16INK4a gene that regulates the G1-S cell cycle checkpoint. Its overexpression could reflect normal proliferative arrest, but also the evolution of carcinogenic processes that have overcome the p16 block, with progression from hyperplasic lesions to invasive breast cancer. Our aim with this study was to correlate p16 expression, both individually and in combination with expression of COX-2 and Ki67, with subsequent risk of breast cancer among women with atypical hyperplasia. Methods: p16 expression was assessed by immunohistochemical assays in archival paraffin-embedded, formalin-fixed sections from 233 women with atypia whose biopsy specimens were obtained via surgical excision at the Mayo Clinic from January 1, 1967, through December 31, 1991. p16 expression was scored as percent of cells positive and intensity of staining. Risk factor information and follow-up for breast cancer events were obtained via study questionnaire and the medical records. Standardized incidence ratios (SIRs) were used to compare observed numbers of breast cancer events to population-based expected counts, both at 10 years and over the entire course of follow-up. Results: Forty-seven patients (20%) developed breast cancer with a mean follow-up of 14.3 (SD=6.96) years. The overall risk of developing breast cancer was not modified by increasing p16 overexpression (low percent of staining with RR=3.89, 95% CI=2.72 to 5.56; high percent of staining with RR=3.91, 95% CI=2.43 to 6.28; similar results for intensity of staining). However, overexpression of both p16 and COX2 conveyed a stronger risk of breast cancer (SIR=4.01, 95% CI 2.28 to 7.07) as compared to dual low expression (SIR 1.78, 95% CI 0.67-4.74). Moreover, overexpression of both Ki67 and p16 was related to a higher 10-year breast cancer risk (SIR 6.25, 95% CI 2.35-16.6) as compared to low expression of both markers (SIR 0.87, 95% CI 0.22-3.49). Conclusions: although single expression of p16 does not stratify breast cancer risk, its overexpression in concert with biomarkers that reflect other carcinogenic processes (e.g. Ki67 and COX2) could help to define risk of tumor development. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 910.

Abstract Background: Uncontrolled proliferation is a defining feature of the malignant phenotype. Ki67 is a marker for proliferating cells and is overexpressed in many breast cancers. Atypical hyperplasia is a premalignant lesion of the breast (relative risk ∼ 4.0). Here we asked if Ki67 expression could stratify risk in women with atypia.Methods: Ki67 expression was assessed immunohistochemically by digital image analysis in archival sections from 192 women with atypia diagnosed at the Mayo Clinic 1/1/67-12/31/91. Risk factor and follow-up data were obtained via study questionnaire and medical records. Observed breast cancer events were compared to population expected rates (Iowa SEER) using standarized incidence ratios (SIRs). We examined both short-term (within 10 years) and long-term (after 10 years) risk of breast cancer (BC) following atypia biopsy.Results: The median value for percent positive cells for Ki67 was 1.0%; the 75th percentile value was 2.3%. Based on the empirical distribution of staining values in our cohort, we selected a cutoff of 2% cells positive to separate high from low staining. There were no differences in Ki67 levels by age at biopsy, type of atypia (ADH, ALH, or both), number of foci of atypia, or family history. 32 women developed BC over a median of 14.6 years. Among them, those with ≥2% Ki67 expression had a shorter time to breast cancer (median 5.5 years, IQR=3.2-7.2) than those with <2% cells positive (median=13.8 years, IQR=11.6-20.3). There was a positive association between Ki67 overexpression (≥2% of cells positive) and risk of BC in the first 10 years of follow-up (SIR=4.42 [95% CI 2.21-8.84]). This excess risk resulted in a 10-year cumulative incidence of 14.1%. In contrast, in the women with low Ki67 expression, we found no increased risk of BC in the first 10 years, with SIR 1.01 (95% CI 0.38-2.70), which was significantly lower than the women with high expression (p=0.01). The 10-year cumulative incidence of BC was 3% for the low Ki67group, in line with population averages. After 10 years, risk increased significantly in the low Ki67 group [SIR 5.69 (3.63-8.92)] vs. no increased risk in the high Ki67 group [SIR 0.78 (0.11-5.55)]. We formally examined this apparent time-dependent difference in incidence patterns by Ki67 staining levels via Poisson regression analysis, and found a statistically significant interaction between pre- vs. post-10 years incidence and high vs. low staining levels (p<0.001).Conclusions: Ki67 appears to be a time-varying biomarker of risk of breast cancer in women with atypical hyperplasia. Women whose atypias show higher proliferation rates have an increased risk for an earlier BC (within 10 years). Those with lower proliferation rates tend to develop BCs later, after 10 years. Ki67 levels may help to define the time period of greatest risk for women with atypia. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 909.

Abstract Background: Risk prediction models are important clinical tools for counseling and decision making for women with an elevated risk of breast cancer, such as women with atypical lobular or ductal hyperplasia (atypia). The Gail model has been shown to underestimate the risk of breast cancer in women with atypia. We sought to evaluate the performance of the Tyrer-Cuzick model in a well-defined cohort of women with atypia.Methods: The Mayo Benign Breast Disease (BBD) Cohort includes 9,376 women aged 18 to 85 who had an open breast biopsy with benign pathological findings between 1967 and 1991. The subset of women with atypia was identified by our study pathologists. Risk factor data required by the Tyrer-Cuzick model were collated for each woman, and the model was used to predict each woman's risk of developing invasive breast cancer within ten years. The predicted numbers of breast cancers were compared to the observed numbers to assess overall model calibration, and the concordance between breast cancer outcomes and predicted probabilities was used to measure the accuracy of the model on the individual level. Subset analysis of women with strong family history was performed. Strong family history was defined as: at least one first-degree relative with breast cancer before the age of 50 years or two or more relatives with breast cancer, at least one being a first degree relative.Results: Three hundred and thirty one women with atypia were identified. Over a mean follow up of 13.7 years, 62 (19%) women have developed invasive breast cancer. Thirty one women developed invasive cancer in the first ten years after biopsy. The Tyrer-Cuzick model predicted that 64.6 invasive breast cancers would occur in the first ten years after biopsy. Thus, the predicted to observed ratio was 2.08 [95% CI: 1.47 – 2.96], p < 0.001).The concordance statistic was 0.51, revealing that the Tyrer-Cuzick model did not accurately distinguish, on an individual level, between women who were diagnosed with invasive breast cancer within ten years of biopsy and those who were not.Performance was somewhat better in the subset of 68 women with a strong family history of breast cancer. The model predicted 12.3 invasive breast cancers, and 7 were observed, for a predicted to observed ratio of 1.76 [95% CI: 0.84 – 3.70]. The concordance statistic was 0.57.Conclusion: The Tyrer-Cuzick model significantly overestimated the risk of breast cancer in the first ten years after biopsy for this group of women with atypia. Individual risk estimates showed poor concordance. Performance was slightly improved in women with a strong family history of breast cancer. Physicians should be cautious when using the Tyrer-Cuzick model to predict ten-year risk in patients with atypia. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6063.

Purpose Accurate breast cancer risk assessment is vital to personalize screening and risk reduction strategies. Women with atypical hyperplasia have a four-fold higher risk of breast cancer. We evaluated the performance of the Tyrer-Cuzick model, which was designed to predict 10-year risk of breast cancer development, in a well-defined cohort of women with atypia. Patients and Methods The Mayo Benign Breast Disease cohort includes 9,376 women who had a benign breast biopsy between 1967 and 1991. Among those, 331 women with atypia were identified by our study pathologists. Risk factor data for the Tyrer-Cuzick model were collated for each woman and used to predict individual risk of developing invasive breast cancer within 10 years. Results Over a median follow-up of 14.6 years, 64 (19%) of the 331 women developed invasive breast cancer. In the first 10 years after biopsy, 31 women developed invasive breast cancer whereas the Tyrer-Cuzick model predicted 58.9. The observed-to-predicted ratio was 0.53 (95% CI, 0.37 to 0.75). The concordance statistic was 0.540, revealing that the Tyrer-Cuzick model did not accurately distinguish, on an individual level, between women who developed invasive breast cancer and those who did not. Conclusion The Tyrer-Cuzick model significantly overestimated risk of breast cancer for women with atypia, and individual risk estimates showed poor concordance between predicted risk and invasive breast cancer development. Thus, we cannot recommend the use of the Tyrer-Cuzick model to predict 10-year breast cancer risk in women with atypical hyperplasia.

Purpose Accurate, individualized risk prediction for breast cancer is lacking. Tissue-based features may help to stratify women into different risk levels. Breast lobules are the anatomic sites of origin of breast cancer. As women age, these lobular structures should regress, which results in reduced breast cancer risk. However, this does not occur in all women. Methods We have quantified the extent of lobule regression on a benign breast biopsy in 85 patients who developed breast cancer and 142 age-matched controls from the Mayo Benign Breast Disease Cohort, by determining number of acini per lobule and lobular area. We also calculated Gail model 5-year predicted risks for these women. Results There is a step-wise increase in breast cancer risk with increasing numbers of acini per lobule (P = .0004). Adjusting for Gail model score, parity, histology, and family history did not attenuate this association. Lobular area was similarly associated with risk. The Gail model estimates were associated with risk of breast cancer (P = .03). We examined the individual accuracy of these measures using the concordance (c) statistic. The Gail model c statistic was 0.60 (95% CI, 0.50 to 0.70); the acinar count c statistic was 0.65 (95% CI, 0.54 to 0.75). Combining acinar count and lobular area, the c statistic was 0.68 (95% CI, 0.58 to 0.78). Adding the Gail model to these measures did not improve the c statistic. Conclusion Novel, tissue-based features that reflect the status of a woman's normal breast lobules are associated with breast cancer risk. These features may offer a novel strategy for risk prediction.

Purpose An accurate estimate of a woman's breast cancer risk is essential for optimal patient counseling and management. Women with biopsy-confirmed atypical hyperplasia of the breast (atypia) are at high risk for breast cancer. The Gail model is widely used in these women, but has not been validated in them. Patients and Methods Women with atypia were identified from the Mayo Benign Breast Disease (BBD) cohort (1967 to 1991). Their risk factors for breast cancer were obtained, and the Gail model was used to predict 5-year–and follow-up–specific risks for each woman. The predicted and observed numbers of breast cancers were compared, and the concordance between individual risk levels and outcomes was computed. Results Of the 9,376 women in the BBD cohort, 331 women had atypia (3.5%). At a mean follow-up of 13.7 years, 58 of 331 (17.5%) patients had developed invasive breast cancer, 1.66 times more than the 34.9 predicted by the Gail model (95% CI, 1.29 to 2.15; P < .001). For individual women, the concordance between predicted and observed outcomes was low, with a concordance statistic of 0.50 (95% CI, 0.44 to 0.55). Conclusion The Gail model significantly underestimates the risk of breast cancer in women with atypia. Its ability to discriminate women with atypia into those who did and did not develop breast cancer is limited. Health care professionals should be cautious when using the Gail model to counsel individual patients with atypia.