Degnim, Amy C.

BACKGROUND Based on its cytologic features, and its co‐occurrence with atypical hyperplasia and breast cancer, flat epithelial atypia (FEA) has been proposed as a precursor lesion on the pathway to the development of breast cancer. It is often referred to as an “atypical” or high‐risk lesion. However, to the authors' knowledge, the long‐term risk of breast cancer in women with FEA is undefined. METHODS Specimens with FEA were identified among excisional breast biopsies in the Mayo Clinic Benign Breast Disease Cohort, which includes 11,591 women who had benign biopsy findings at the Mayo Clinic in Rochester, Minnesota between 1967 and 2001. Breast cancer risk among subsets of patients with FEA and nonproliferative, proliferative, and atypical hyperplasia (AH) was assessed using standardized incidence ratios (SIRs) compared with the Iowa Surveillance, Epidemiology, and End Results registry. RESULTS FEA was identified in 282 women (2.4%); 130 had associated AH (46%) and 152 (54%) were classified as having proliferative disease without atypia (PDWA). With median follow‐up of 16.8 years, the SIR for breast cancer in patients with AH plus FEA was 4.74 (95% confidence interval [95% CI], 3.17‐6.81) versus 4.23 (95% CI, 3.44‐5.13) for those with AH without FEA ( P = .59). The SIR for patients with PDWA plus FEA was 2.04 (95% CI, 1.23‐3.19) versus 1.90 (95% CI, 1.72‐2.09) for patients with PDWA without FEA ( P = .76). CONCLUSIONS FEA is an uncommon finding in women with benign breast disease. FEA does not appear to convey an independent risk of breast cancer beyond that of the associated PDWA or AH. Cancer 2015;121:1548–1555 . © 2015 American Cancer Society .

Abstract Background: Women with benign breast disease (BBD) have increased breast cancer risk, and histologic features of the lesion stratify individual risk. We hypothesized that the concentration and type of terminal duct lobular units in BBD tissue is associated with future breast cancer risk. Methods: A nested case-control series of 770 breast cancer cases and 1273 age- and year of biopsy-matched controls was identified within a cohort of 13,647 women with BBD from 1967-2001 (median follow-up 15.3 years). One representative H&E slide from each biopsy was reviewed by a single pathologist, who recorded total # of lobules present, and # of fibrocystic lobules (total and # with epithelial proliferation). Samples were also evaluated for lobular involution and primary BBD histology. Lobule density (LD) was calculated as # of lobules/cm2 in each tissue section. Breast cancer associations with LD's (total, fibrocystic, proliferative) were examined with conditional logistic regression. Odds ratios are reported per 1 SD increase in LD. Results: Each LD measure was significantly associated with involution and primary BBD histology (p<0.0001 for each). Fibrocystic (OR 1.17, 95% CI 1.06-1.28) and proliferative (OR 1.37, 95% CI 1.16-1.61) LD were each associated with case status (p≤0.001) but total LD did not reach significance (OR 1.09, 95% CI 1.0-1.20; p=0.06). LD associations were somewhat attenuated after adjusting for involution (total OR 1.04 p=0.41; fibrocystic OR 1.13 p=0.02; proliferative OR 1.28 p=0.002) and primary BBD histology (total OR 1.04 p=0.49; fibrocystic OR 1.08 p=0.15; proliferative OR 1.18 p=0.07). Conclusions: The density of proliferative lobules in benign breast biopsy tissue is related to other BBD histologic features but may provide additional breast cancer risk stratification among women with proliferative BBD. Additional research will more fully evaluate the ability of this promising novel measure to predict breast cancer risk. Lobule Density Measures (lobules per square cm) All values are Medians Total Lobule Density Fibrocystic Lobule Density Proliferative Lobule Density Overall 17.5 4.5 0.7 Cases 18.1 4.9 1.3 Controls 17.0 4.2 0.4 Primary BBD Histology Nonproliferative disease 16 3.3 0 Proliferative disease 18.6 5.8 2.7 Atypical hyperplasia 20.9 6.2 3.3 Involution Category None 28.7 5.3 1.0 Partial 19.0 5 1.2 Complete 8.5 2.1 0 Citation Format: Amy C. Degnim, Lynn C. Hartmann, Tanya L. Hoskin, Marlene H. Frost, V Shane Pankratz, Derek C. Radisky, Lorelle L. Benetti, Celine M. Vachon, Teresa M. Allers, Robert A. Vierkant, Daniel W. Visscher. Density of breast lobules in benign breast tissue and association with future breast cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 155. doi:10.1158/1538-7445.AM2013-155

Abstract Background: Current options to prevent ovarian and breast cancer recurrence are limited. However, signs of anti-tumor immunity are associated with improved survival in patients who have experienced a number of different malignancies. After identifying folate receptor alpha (FR)-derived class II-binding peptides recognized by lymphocytes from patients who previously had breast or ovarian cancer, we developed a multi-peptide vaccine with five peptides, each of which was recognized by more than 25% of the patients. We combined this vaccine with metronomic cyclophosphamide in an attempt to selectively reduce T regulatory cells in the periphery and the tumor microenvironment. Methods: We obtained an Investigational New Drug approval from the Food and Drug Administration to perform a phase I study in 22 patients who were currently in remission from their breast or ovarian cancer. Participants were required to be at least 90 days past any treatment for their disease (other than hormonal treatment, if applicable) and show no current evidence of disease. After 28 days of metronomic cyclophosphamide, six monthly intradermal injections of the vaccine were given. The primary endpoints of the trial are safety and immunogenicity. Results: To date, 15 of 22 patients have enrolled (7 breast and 8 ovarian cancer patients). 4 breast and 2 ovarian cancer patients are available for toxicity evaluation. No serious major adverse events have been observed, with the expected injection site reactions being the primary toxicity experienced by most participants; grade 2 decreased white blood cell counts were observed in 3 patients at completion of cyclophosphamide. Two patients went off study prior to completing all six vaccinations, one for vision changes, and one for disease progression. Immune monitoring is underway, with major assays being ELISAs for high-affinity IgG targeting the FR and FR-peptide specific ELIspots. These data will be presented at the meeting. Conclusions: Metronomic cyclophosphamide followed by intradermal vaccinations with a multi-peptide vaccine targeting the tumor antigen FR appears to be a tolerable regimen at this preliminary point of the study. With the exception of vision changes in one patient, no serious safety concerns have arisen. Pursuit of this strategy in further clinical study will require demonstration of FR-specific immune responses, an acceptable toxicity profile, and demonstration that T regulatory cells are altered in the periphery. Citation Format: Kimberly R. Kalli, Courtney L. Erskine, James W. Krempski, Linda M. Benson, Vera J. Suman, Douglas J. Padley, Allan B. Dietz, Timothy J. Hobday, Amy C. Degnim, Lynn C. Hartmann, Matthew S. Block, Keith L. Knutson. Metronomic cyclophosphamide followed by a multi-peptide folate receptor vaccine for ovarian and breast cancer immunotherapy in the setting of minimal residual disease - a feasibility study. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A82.

Abstract Atypical hyperplasia is a high-risk premalignant lesion of the breast, but its biology is poorly understood. Many believe that atypical ductal hyperplasia (ADH) is a direct precursor for low-grade ductal breast cancer, whereas atypical lobular hyperplasia (ALH) serves as a risk indicator. These assumptions underlie current clinical recommendations. We tested these assumptions by studying the characteristics of the breast cancers that develop in women with ADH or ALH. Using the Mayo Benign Breast Disease Cohort, we identified all women with ADH or ALH from 1967 to 2001 and followed them for later breast cancers, characterizing side of breast cancer versus side of atypia; time to breast cancer; type, histology, and grade of breast cancer, looking for patterns consistent with precursors versus risk indicators. A total of 698 women with atypical hyperplasia were followed a mean of 12.5 years; 143 developed breast cancer. For both ADH and ALH, there is a 2:1 ratio of ipsilateral to contralateral breast cancer. The ipsilateral predominance is marked in the first 5 years, consistent with a precursor phenotype for both ADH and ALH. For both, there is a predominance of invasive ductal cancers with 69% of moderate or high grade. Twenty-five percent are node positive. Both ADH and ALH portend risk for ductal carcinoma in situ and invasive breast cancers, predominantly ductal, with two thirds moderate or high grade. The ipsilateral breast is at especially high risk for breast cancer in the first 5 years after atypia, with risk remaining elevated in both breasts long term. ADH and ALH behave similarly in terms of later breast cancer endpoints. Cancer Prev Res; 7(2); 211–7. ©2014 AACR.

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.