Citations

Abstract Background: Women with hereditary breast cancer risk, who develop breast cancer, face complex surgical decisions related to their breast cancer and risk to their contralateral breast. The aim of this study was to prospectively evaluate the factors influencing decision making in these women and degree of decision conflict before and after consultation with breast specialized physicians (BSP). Methods: Women with hereditary breast cancer risk and recently diagnosed with unilateral breast cancer were enrolled in a prospective decision making questionnaire study. Questionnaires were completed prior to their initial breast clinic visit and after consultation with a breast clinic physician, nurse educator and a breast surgeon. Results: 68 women completed both questionnaires. Mean age was 52 (range 27–84). Prior to meeting with BSP, 10 (15%) women reported having made a decision for the cancer side and 18 (26%) reported being close to deciding. Of the 20 who expressed a surgical preference prior to consultation, 5 (25%) changed their decision after meeting with the BSP [1 to mastectomy (MTX), 4 to breast conservation (BC)]. After consultation with BSP, 65 (96%) reported having made a decision (BC in 29 (45%), MTX in 35 (54%), unspecified in one). The most commonly cited reasons influencing surgical choice were doctor's advice (79%), family history of breast cancer (74%) and worrisome findings on biopsy (50%). Prior to meeting with BSP, 9 (13%) women reported having made a decision regarding screening and/or risk-reducing options for the contralateral breast and another 11 (16%) reported being close to a decision. The choices in these 20 women were screening only in 10 (50%), contralateral prophylactic MTX (CPM) in 3 (15%), CPM and oophorectomy in 2 (10%), other combinations of options in 4, and unspecified in 1. After meeting with the BSP, 49 (72%) reported having made a decision regarding the contralateral breast; this decision was for screening only in 21 (43%), CPM only in 9 (18%), screening plus tamoxifen in 7 (14%), CPM and oophorectomy in 2 (4%), other combinations of options in 8, and unspecified in 2. The most commonly cited reasons for choices on the contralateral side were: family history (81%), doctor's advice (78%), and worrisome findings on biopsy (43%); only 25% cited psychological or emotional reasons. For both the cancer and contralateral sides, decisional conflict was significantly lower after meeting with BSP than prior to meeting with BSP. Decision-conflict scale total scores (possible range 0–100; higher scores indicate more decisional conflict) summarized for each side and compared between timepoints Conclusion: The BSP consult and family history have the greatest influence on decision making among women with hereditary risk diagnosed with breast cancer. After consultation most women felt they had made decisions for both the cancer and contralateral sides and reported significantly lower decision conflict compared to prior to the consultation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-15-05.

Purpose Contralateral prophylactic mastectomy (CPM) rates in women with unilateral breast cancer are increasing despite controversy regarding survival advantage. Current scrutiny of the medical costs led us to evaluate the cost-effectiveness of CPM versus routine surveillance as an alternative contralateral breast cancer (CBC) risk management strategy. Methods Using a Markov model, we simulated patients with breast cancer from mastectomy to death. Model parameters were gathered from published literature or national databases. Base-case analysis focused on patients with average-risk breast cancer, 45 years of age at treatment. Outcomes were valued in quality-adjusted life-years (QALYs). Patients' age, risk level of breast cancer, and quality of life (QOL) were varied to assess their impact on results. Results Mean costs of treatment for women age 45 years are comparable: $36,594 for the CPM and $35,182 for surveillance. CPM provides 21.22 mean QALYs compared with 20.93 for surveillance, resulting in an incremental cost-effectiveness ratio (ICER) of $4,869/QALY gained for CPM. To prevent one CBC, six CPMs would be needed. CPM is no longer cost-effective for patients older than 70 years (ICER $62,750/QALY). For BRCA-positive patients, CPM is clearly cost-effective, providing more QALYs while being less costly. In non-BRCA patients, cost-effectiveness of CPM is highly dependent on assumptions regarding QOL for CPM versus surveillance strategy. Conclusion CPM is cost-effective compared with surveillance for patients with breast cancer who are younger than 70 years. Results are sensitive to BRCA-positive status and assumptions of QOL differences between CPM and surveillance patients. This highlights the importance of tailoring treatment for individual patients.

Abstract Purpose: Emerging data from cooperative group trials suggests that not all patients with a positive SLN require completion axillary lymph node dissection (ALND). The controversy regarding who will benefit from additional nodal clearance continues, suggesting a need for improved tools to predict non-SLN involvement. We hypothesized that the size of a SLN metastasis evaluated as a continuous variable would be an important predictor of non-SLN involvement. The goal of this study was to determine clinicopathologic factors including SLN metastasis size that predicted non-SLN involvement and to use these factors to construct an improved predictive nomogram. Methods: Using a prospective database, we identified 509 patients with invasive breast cancer from 1996 - 2007 with a positive SLN who underwent ALND. Patients receiving neoadjuvant therapy were excluded. Clinicopathologic data including age, primary tumor size, presence of multifocal disease, histology (invasive ductal vs. invasive lobular vs. mixed invasive), tumor grade, estrogen receptor, progesterone receptor, and HER2/neu status, presence of lymphovascular invasion (LVI), the number of SLNs identified, number of positive SLNs, the maximum SLN metastasis size and the presence of extranodal extension were recorded. For SLNs described only as containing isolated tumor cells, size was recorded as 0.1 mm. Univariate and multivariate logistic regression analyses were performed to identify factors predictive of positive non-SLNs. Using these variables, a nomogram was constructed and subsequently validated using an external cohort of 464 patients. Results: On univariate analysis, the following factors were predictive of positive non-SLNs: number of SLN identified (p<.001), number of positive SLN (p<.001), maximum SLN metastasis size (p<.001), extranodal extension (p<.001), primary tumor size (p=.001), LVI (p=.019) and histology (p=.034). On multivariate analysis, all factors remained significant at the 5% level except LVI. A nomogram was created using these variables. When applied to an external cohort, the nomogram was accurate and discriminating with an area under the receiver operating characteristic curve of .73 (95% CI: .68 - .77). Conclusions: SLN metastasis size is predictive for identifying additional disease in the axilla. These data have been incorporated into a nomogram that accurately predicts the likelihood of having additional, non-SLN metastasis suggesting that routine reporting of the SLN metastasis size would assist with clinical decision making regarding the need to perform a completion ALND. Figures available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-08.

Abstract INTRODUCTION: Surgical site infection (SSI) is a problematic cause of morbidity following breast/axillary surgery. The breast/axilla has a higher rate of SSI than expected for clean wounds. We evaluated risk factors associated with SSI after breast/axillary operations. Methods: A retrospective review of breast/axillary procedures from July 2004 to July 2006 was performed. SSI was defined using Centers for Disease Control and Prevention criteria, including cases with cellulitis as the only criterion of infection. Data collected included patient demographics, BMI, surgical procedure, ASA class, antibiotic use, drains, and prior radiation (RT). RESULTS: We identified 389 patients who underwent 678 procedures. Thirty-seven SSI (5.5% of procedures) were identified, of which 24 (65%) had only cellulitis. Median time from surgery to SSI diagnosis was 9 days (range 2-112), with 81% occurring in the first 30 days. Univariate analysis identified prior RT, BMI, type of procedure, operative time, use of drain, and postoperative seroma to be associated with SSI (all P<0.05). With multivariate analysis, procedure type remained significant overall (p=0.04). Specifically, mastectomy with sentinel lymph node biopsy (SLNB) and modified radical mastectomy remained significantly associated with higher risk of SSI, with hazard ratios (HR) of 6.3 and 13.5 fold respectively compared to SLNB alone. Seroma (HR 9.0, 95% CI 2.7-29.3), prior RT (HR 3.4, 1.2-9.9), and BMI >=30 (HR 3.1, 1.6-6.2) also remained significantly associated with SSI. CONCLUSION(S): SSI are more frequent after breast/axillary operations than other clean wounds and are associated with prior RT, obesity, more extensive and longer procedures, and postoperative seroma. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-10.

Abstract Background Local recurrence after breast conservation surgery (BCS) varies with clinical risk factors. The aim of this study was to evaluate how local recurrence rates vary by patient age at time of BCS. Methods With IRB approval, all patients undergoing BCS for primary breast cancer between 1988 and 2001 at Mayo Clinic, Rochester were identified. Patients receiving neoadjuvant chemotherapy were excluded. Local recurrence-free survival rates were estimated using the Kaplan-Meier method. Associations with local recurrence-free survival were evaluated using log-rank tests and Cox proportional hazards regression models. Results 3,075 patients underwent 3,143 BCS between 1988 and 2001. Mean age at BCS was 61 years (range 21-98). There were 177 (5.6%) patients aged <40, 496 (15.8%) 40-49, 763 (24.3%) 50-59, 803 (25.6%) 60-69, and 904 (28.8%) who were 70+ years old at time of surgery. At last follow-up, 214 patients (6.9%) experienced a local recurrence at a median of 3.4 years following BCS (range 0.1-14.4). Median follow-up for patients who did not experience a local recurrence was 8.7 years (range 0.0-20.2). The 5-year local recurrence-free survival rate was 95.0%. The frequency of local recurrences by age group were as follows: age <40 — 11.9%; age 40-49 — 5.9%; age 50-59 — 5.9%; age 60-69 — 7.6%; age 70 and older — 6.4%. The 5-year local recurrence-free survival rates for these age groups were 90.0%, 95.4%, 95.6%, 95.4%, and 94.7%, respectively (p=0.041; log-rank test). On univariate analysis, patients <40 years old were nearly twice as likely to experience a local recurrence following BCS compared with patients DCIS was associated with an increased risk of local recurrence compared with T1, T2, T3, or T4 disease (HR 2.25; P<0.001). Factors associated with a decreased risk of local recurrence on univariate analysis included ER positivity (HR 0.46; P<0.001), PR positivity (HR 0.60; p=0.001), adjuvant radiation (HR 0.48; p=0.007) and endocrine therapy (HR 0.65; p=0.012). Multivariate analysis of patients with complete data (n=2126) demonstrated that age <40 and node positivity were associated with an increased risk of local recurrence, while ER positivity, adjuvant radiation and endocrine therapy were associated with a decreased risk of local recurrence. Multivariable analysis of local recurrence after BCS Conclusion Risk factors for local recurrence after BCS include young age, node positivity, ER and PR negativity and absence of adjuvant radiation and endocrine therapy. Patients under age 40 are at increased risk of local recurrence following BCS for breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-10-02.

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: 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.

Abstract Abstract #62 Background: Breast cancer is the leading cause of cancer deaths in younger women (25 to 49 years of age). Young women with breast cancer also have worse overall survival and increased risk of recurrence compared to older women with breast cancer. Innovative approaches to understanding risk factors and tissue characteristics for the younger population can improve understanding of breast cancer etiology and enhance risk-stratification for these women. This study was aimed at examining breast cancer risk factors among young women (<50 years) with BBD. Materials and Methods: Utilizing the Mayo Clinic Surgical and Pathology Indices, women ages 18 to 85 who had benign excisional breast biopsy between January 1, 1967 and December 31, 1991 were identified. The diagnosis of breast cancer served as the study endpoint and was determined using the Mayo medical record and questionnaire information from study participants. The breast pathologist, blinded to the initial diagnosis and clinical outcome, performed pathology review. BBD was classified as non-proliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). Age-related lobular involution (reduction in number and size of acini per lobule) was classified as none-0%, partial- 1 to74%, or complete- >75% involution. Relative risk (RR) was estimated by comparing the number of observed breast cancers with the number expected, based on breast cancer rates in the Iowa Surveillance, Epidemiology, and End Results registry. Results: Of the 9376 women in the Mayo BBD cohort, 4460 women were aged <50 years at BBD diagnosis and formed the study cohort. The mean age at BBD diagnosis was 39.4 (+ 8.3) years. With a median follow-up of 20 years, 326 breast cancer cases were identified. The histologic findings were NPD in 72% of women, PDWA in 26%, and AH in 2%. The relative risk of breast cancer for the overall cohort of young women with BBD was 1.5 (95% CI [1.4, 1.7]). The relative risk among those with AH was 6.9 (95% CI [4.6, 10.1), compared with a RR of 2.0 (95% CI [1.7, 2.4]) for PDWA, and RR of 1.2 (95% CI [1.0, 1.4]) for NPD. Risk was associated with extent of lobular involution (RR for no involution was 1.7 (95%CI [1.4, 2.1]); partial involution 1.4 (95%CI [1.2, 1.7]); complete involution 0.7 (95%CI [0.3, 1.4]). Family history was available for 83% of the cohort and RR was 2.2 (95% CI [1.7, 2.8]) for women with strong family history and was 1.3 (95% CI [1.1, 1.6]) for women with no family history. Discussion: Young women with BBD are at increased risk of breast cancer. Risk is high in women with atypical hyperplasia, and those with a family history of breast cancer. Lobular involution is associated with reduced breast cancer risk in this population, suggesting a role in modifying breast cancer risk. These findings suggest the need for further research in this population, along with tissue-based studies to examine the processes leading to breast cancer, and enable identification of those women at highest risk. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 62.