Benign Breast Biopsy Research Articles

Follow-up outcomes after benign concordant MRI-guided breast biopsy

ObjectiveTo evaluate outcomes of benign concordant magnetic resonance imaging (MRI)-guided breast biopsy. MethodsWe retrospectively reviewed 611 consecutive MRI-guided breast core biopsies at our institution from 2005 to 2012. Benign concordant cases with MRI follow-up constituted the study group. Lesion appearance on follow-up MRI was assessed and the false-negative rate was calculated. ResultsEighty-four lesions in 68 women underwent benign concordant MRI-guided biopsy with subsequent MRI follow-up. Mean time to first follow-up MRI was 10.5 months. Two false negatives were identified on follow-up at 8 and 26 months. ConclusionsWe report a false-negative rate of MRI-guided breast biopsy of 2.4%.

Assessing the Relationship of Mammographic Breast Density and Proliferative Breast Disease.

Increased breast density and a history of benign breast biopsy are both considered risk factors for developing breast cancer. Understanding the specifics of these risk factors and their relationship to each other can lead to a better understanding of a patient's propensity for breast cancer development and improved surveillance strategies. We included 245 women who underwent a benign breast biopsy without atypia between October 2011 and June 2013. Biopsies were performed for suspicious calcifications as well as masses and architectural distortion. Lesions biopsied were divided into two groups: calcified and noncalcified lesions. The patient's breast density was assessed on most recent mammogram and was classified using the American College of Radiology BI-RADS density categories. Based on histologic diagnosis, each case was classified as proliferative or nonproliferative breast disease. The median age of the cohort (n = 245) was 55 years (range, 40-84 years). There were 162 (66%) postmenopausal women in the study. A core biopsy was performed for calcifications in 33.5% cases and for noncalcified lesions in 58% cases. In patients with dense breast tissue, an underlying proliferative histology was found significantly more frequently with calcifications (66.7%) as opposed to noncalcified lesions (35.9%) (RR = 2.3 (1.3-4.0); χ(2) = 8.7; p = 0.003). In nondense breast patients, there was no significant difference (RR = 1.1 (0.7-1.8); χ(2) = 0.1; p = 0.738). In the postmenopausal group, women with dense breasts had proliferative histology significantly more frequently than women with nondense breasts (55.3% versus 38.3%; p < 0.05), regardless of the underlying lesion type. Postmenopausal women with dense breasts who underwent a breast biopsy with benign histology had a significantly higher likelihood of having proliferative breast disease, regardless of underlying lesion type. Women with dense breasts also showed proliferative histology significantly more often for calcifications as opposed to noncalcified lesions.

Factors Associated With Rates of False-Positive and False-Negative Results From Digital Mammography Screening: An Analysis of Registry Data

Women screened with digital mammography may receive false-positive and false-negative results and subsequent imaging and biopsies. How these outcomes vary by age, time since the last screening, and individual risk factors is unclear. To determine factors associated with false-positive and false-negative digital mammography results, additional imaging, and biopsies among a general population of women screened for breast cancer. Analysis of registry data. Participating facilities at 5 U.S. Breast Cancer Surveillance Consortium breast imaging registries with linkages to pathology databases and tumor registries. 405,191 women aged 40 to 89 years screened with digital mammography between 2003 and 2011. A total of 2963 were diagnosed with invasive cancer or ductal carcinoma in situ within 12 months of screening. Rates of false-positive and false-negative results and recommendations for additional imaging and biopsies from a single screening round; comparisons by age, time since the last screening, and risk factors. Rates of false-positive results (121.2 per 1000 women [95% CI, 105.6 to 138.7]) and recommendations for additional imaging (124.9 per 1000 women [CI, 109.3 to 142.3]) were highest among women aged 40 to 49 years and decreased with increasing age. Rates of false-negative results (1.0 to 1.5 per 1000 women) and recommendations for biopsy (15.6 to 17.5 per 1000 women) did not differ greatly by age. Results did not differ by time since the last screening. False-positive rates were higher for women with risk factors, particularly family history of breast cancer; previous benign breast biopsy result; high breast density; and, for younger women, low body mass index. Confounding by variation in patient-level characteristics and outcomes across registries and regions may have been present. Some factors, such as numbers of first- and second-degree relatives with breast cancer and diagnoses associated with previous benign biopsy results, were not examined. False-positive mammography results and additional imaging are common, particularly for younger women and those with risk factors, whereas biopsies occur less often. Rates of false-negative results are low. Agency for Healthcare Research and Quality and National Cancer Institute.

Human Papilloma Viruses and Breast Cancer.

Human papillomaviruses (HPV) may have a role in some breast cancers. The purpose of this study is to fill important gaps in the evidence. These gaps are: (i) confirmation of the presence of high risk for cancer HPVs in breast cancers, (ii) evidence of HPV infections in benign breast tissues prior to the development of HPV-positive breast cancer in the same patients, (iii) evidence that HPVs are biologically active and not harmless passengers in breast cancer. RNA-seq data from The Cancer Genome Atlas (TCGA) was used to identify HPV RNA sequences in breast cancers. We also conducted a retrospective cohort study based on polymerase chain reaction (PCR) analyses to identify HPVs in archival specimens from Australian women with benign breast biopsies who later developed breast cancer. To assess whether HPVs in breast cancer were biologically active, the expression of the oncogenic protein HPV E7 was assessed by immunohistochemistry (IHC). Thirty (3.5%) low-risk and 20 (2.3%) high-risk HPV types were identified in 855 breast cancers from the TCGA database. The high risk types were HPV 18 (48%), HPV 113 (24%), HPV 16 (10%), HPV 52 (10%). Data from the PCR cohort study indicated that HPV type 18 was the most common type identified in breast cancer specimens (55% of 40 breast cancer specimens) followed by HPV 16 (13%). The same HPV type was identified in both the benign and subsequent breast cancer in 15 patients. HPV E7 proteins were identified in 72% of benign breast specimens and 59% of invasive breast cancer specimens. There were four observations of particular interest: (i) confirmation by both NGS and PCR of the presence of high-risk HPV gene sequences in breast cancers, (ii) a correlation between high-risk HPV in benign breast specimens and subsequent HPV-positive breast cancer in the same patient, (iii) HPVs in breast cancer are likely to be biologically active (as shown by transcription of HPV DNA to RNA plus the expression of HPV E7 proteins), (iv) HPV oncogenic influences may occur early in the development of breast cancer.

Is 6-Month Radiologic Imaging Necessary after Benign Breast Biopsy? Review of Literature and Multicenter Experience

A retrospective study of 786 patients was conducted to determine the necessity of a 6-month interval study after a benign stereotactic or ultrasound-guided breast biopsy. These results were compared with those of other centers. After reviewing the data, we found few patients developed cancer after their original biopsy, and for those that did, the 6-month study did not contribute to an earlier diagnosis. Those short-term interval radiologic studies that were interpreted as concerning were all benign when biopsied. A 6-month study contributes to higher costs of health care and can be inconvenient, painful, and anxiety producing to patients. Short-interval follow-up was found to be unnecessary.

Abstract A2-03: Hotspot mutation in breast benign biopsy associated with subsequent progression to malignant breast cancer

Abstract Background: Breast cancer prevention is currently in a challenge due to the inability to identify high-risk women accurately only based on family history and pathologic evaluation of benign biopsy. Somatic molecular changes in clinically normal breasts have potential value for to improve the assessment of truly high-risk women. The identification of risk biomarkers in benign biopsy material will directly benefit the millions of women who undergo benign breast biopsy annually, adding precision to the risk implied by the histologic features of the benign biopsy. Therefore, we are pursuing robust biomarkers for breast cancer risk by sequencing pre-cancer benign biopsies, which may lead to discovery of genomic variation responsible for initiation and early progression of breast cancer. Methods: We are assembling a case-control set of benign breast biopsy matched by age, race, and duration of follow-up. The cases were the benign biopsies from women who subsequently developed breast cancer after at least one year, and the controls were the benign biopsy samples obtained from women who remain cancer free. 10-micron sections from formalin-fixed, paraffin-embedded tissue blocks are used for laser capture microdissection of selected epithelial areas and extraction of DNA. As a pilot experiment, we examined hotspot mutation in 4 cases and 4 control samples, using Ion AmpliSeq cancer hotspot panel consisting of 50 oncogenes/tumor suppressor and detecting 2855 hotspot mutation from COSMIC (Catalogue Of Somatic Mutations In Cancer). The average amplicon length was 154 (111-187) with average depth coverage of 1400x. SNP detection sensitivity was 98% for 5% variant frequency. Results: Among the 2855 hotspot mutation in 50 oncogenes/tumor suppressor detected, 153 mutation in 27 genes were identified in cases, and 62 mutations in 18 genes were found in controls. The most frequent mutanted gene was TP53 (71 mutation in cases, 24 mutation in controls). In 6 genes (CTNNB1, CDKN2A, ATM, KRAS, STK11 and SMARCB1), hotspot mutation was identified in at least two cases, but no hotspot mutation was identified in controls. Among the 4 cases, one cases had 95 hotspot mutation, much higher than the other 3 cases (5, 16, 37 mutation, respectively) and 4 controls (8, 11, 14, 29 mutation, respectively). This case progressed to triple negative (ER-, PR-, HER2-) breast cancer, a very aggressive subtype of cancer with poor prognosis. Conclusion: The pilot study of deep sequencing of breast benign biopsy suggested that the overall hotspot mutation frequency was higher in cases which progressed to malignant cancer compared to controls which did not progress to malignant cancer. Several genes were identified to be specifically associated with the progression. Citation Format: Jun Wang, Gang Feng, Nadereh Jafari, Ali Shidfar, David Ivanicic, Megan E. Sullivan, Seema A. Khan. Hotspot mutation in breast benign biopsy associated with subsequent progression to malignant breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-03.

Breast cancer risk by extent and type of atypical hyperplasia: An update from the Nurses' Health Studies.

Women with atypical hyperplasia (AH) on a benign breast biopsy specimen are at increased risk for the development of breast cancer. However, the relation between the type and extent of AH (atypical ductal hyperplasia [ADH] vs atypical lobular hyperplasia [ALH]) and the magnitude of the breast cancer risk is not well defined. A nested case-control study of benign breast disease and breast cancer risk was conducted. Women with breast cancer and prior benign breast biopsy findings (488 cases) were matched to women with prior benign breast biopsy findings who were free from breast cancer (1907 controls). Benign breast biopsy slides were reviewed and categorized as nonproliferative, proliferative without atypia, or AH (ADH or ALH). The number of foci of AH was also recorded. Among women with ADH, the interrelation between the extent of atypia and breast cancer risk was not significant (odds ratio [OR] for 1 or 2 foci, 3.5; 95% confidence interval [CI], 2.2-5.6; OR for ≥3 foci, 2.7; 95% CI, 1.4-5.1; P = .41). Similarly, although the risk with ALH was higher for those with ≥3 foci than for those with <3 foci, the difference was not statistically significant (OR for 1 or 2 foci, 5.2; 95% CI, 2.7-10.0; OR for ≥3 foci, 8.0; 95% CI, 4.5-14.2; P = .19). This analysis demonstrates that the extent of ADH or ALH does not significantly contribute to breast cancer risk. The lack of a significant dose-response relation between the extent and type of atypia and breast cancer risk suggests that it would be premature to use the extent of atypia to influence management decisions for women with ADH or ALH.

Abstract B34: CD56+ immune cell infiltration is decreased in benign breast lobules with fibrocystic changes

Abstract Introduction: CD56+ lymphocytes (a defining marker of natural killer cells) have a predominantly cytotoxic phenotype and a hypothetical role in breast tumor immunosurveillance. Here we investigate whether CD56+ staining density varies in nonmalignant breast lobules according to confirmed breast cancer risk factors- age, and histologic features of fibrocystic change and lobular involution. Methods: Archived breast tissue samples were obtained from 94 women with benign breast disease (BBD). The sample set was selected as a nested case-control study (47 cases, 47 controls) from within a large BBD cohort; cases were those who developed breast cancer subsequent to their benign breast biopsy; controls were matched to cases on age at biopsy, year of biopsy, and length of breast cancer free follow-up at least as long as the time-to-cancer in the matched case. Up to 10 representative lobules in each sample were characterized by H&amp;E for fibrocystic changes and the degree of epithelial proliferation (normal, nonproliferative, proliferative, atypia) and for degree of lobular involution (none, partial, complete). Consecutive sections were immunostained for CD56 and hematoxylin. Using digital image analysis, CD56 staining was quantified on a per lobule basis by pixel ratio (PR) (positive stain:total lobule). Statistical analysis was performed using linear mixed effects regression on the rank transformed density to account for correlations among multiple lobules from the same patient in assessing the association of density with lobule characteristics and using conditional logistic regression for association with case-control status. Results: Among 94 women (median age 52, range 35-73), 876 lobules were evaluated: 431 in BBD cases and 445 in BBD controls. Overall, 391 lobules (45%) were normal and the remaining 485 (55%) demonstrated fibrocystic changes. Among fibrocystic lobules, 247 (51%) had nonproliferative changes, 218 (45%) had epithelial proliferation, and 20 (4%) had atypical hyperplasia. Among normal lobules, 61 (16%) had no involution, 139 (36%) had partial involution, and 191 (49%) had complete involution. The vast majority of lobules (861/876, 98%) demonstrated presence of CD56+ cells, while only 15 of 876 lobules in 11 patients had zero CD56+ cells [7 cases (15%) versus 4 controls (8.5%) OR 1.75, p = 0.37]. The median CD56+ PR was 0.55% overall. Fibrocystic lobules as a group showed significantly lower median CD56+ PR compared to normal lobules (0.37% vs 0.85%, p &amp;lt; 0.0001). Among subcategories of fibrocystic lobules, the median CD56+ PR was lower in proliferative lobules (0.29%) compared to non-proliferative (0.42%), but this difference was not statistically significant (p = 0.55). Older women (age &amp;gt; 55) showed the highest CD56+ PR (median of 0.92%), as compared to 0.38% in women 45-55 (p=0.02), and 0.52% in women age &amp;lt;45 (p = 0.26). Among normal lobules, median CD56+ PR was similar between lobules with no involution (0.55%) and partial involution (0.52%) but was considerably higher among lobules with complete involution (1.3%, p = 0.09 and p = 0.05, respectively). In a multivariable model, CD56+ PR differences between fibrocystic and normal lobules remained significant (p = 0.0002) and also remained significant between age groups of &amp;gt; 55 and 45-55 (p = 0.02), while involution was non-significant. Median CD56+ PR was lower in cases (0.43%) compared to controls (0.72%), but this was not statistically significant (p=0.19) in our sample of 47 case-control pairs. Conclusions: Breast lobules with fibrocystic changes show less CD56+ cells, raising a question of possible immune suppression induced by early epithelial abnormalities. These findings encourage further investigation to improve understanding of the immune microenvironment in premalignant breast tissues. Citation Format: Rushin D. Brahmbhatt, Daniel Kerekes, Tanya L. Hoskin, Alvaro Pena, Daniel W. Visscher, Melody L. Stallings-Mann, Derek C. Radisky, Linda M. Murphy, Vernon Shane Pankratz, Keith L. Knutson, Marlene Frost, Amy C. Degnim. CD56+ immune cell infiltration is decreased in benign breast lobules with fibrocystic changes. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B34.

The Management of Benign Concordant MRI-guided Breast Biopsies: Lessons Learned

After benign concordant magnetic resonance imaging (MRI)-guided breast biopsy, initial follow-up MRI at 6 months is often recommended for confirmation. This study was undertaken to determine the proper management of stable lesions on initial follow-up MRI and whether such follow-up can be safely deferred to 12 months. Retrospective review of 240 MRI-guided biopsies identified 156 benign concordant lesions. 85 eligible cases received follow-up MRI and constitute the study population. On initial follow-up MRI, 72 of 85 lesions appeared adequately sampled, 12 were stable and underwent further MRI follow-up, and 1 was benign on subsequent surgery. No cancers were diagnosed at the biopsy sites on either 6- or 12-month follow-up MRI. Among the 12 stable lesions, four were masses and eight were nonmass enhancements. One of the stable masses enlarged on 24-month follow-up MRI and proved malignant. All stable nonmass lesions were benign on long-term follow-up. After benign concordant MRI-guided breast biopsy, a stable mass has a 25% probability of malignancy in our series. Re-biopsy of such masses should be strongly considered. Stable nonmass lesions may be followed with subsequent MRI without rebiopsy. Deferral of initial follow-up MRI to 12 months may be acceptable.

Abstract P6-10-06: Histologic features of benign breast biopsy tissue and association with ER positive and ER negative breast cancer in the Mayo BBD cohort study

Abstract Introduction: Current models to predict breast cancer risk do not differentiate risk for estrogen receptor (ER) positive and negative breast cancer (BC), despite growing evidence that these tumors are biologically very different. We hypothesized that women with ER+ BC cancers have different clinical risk factors and histologic findings on prior benign breast biopsies than those with ER- BC. Methods: After IRB approval, we examined associations of age at benign biopsy and histologic features of the benign biopsy with ER status of incident BCs within the Mayo Benign Breast Disease Cohort. Benign biopsy slides were reviewed for extent of lobular involution and degree of epithelial proliferation by a single breast pathologist blinded to BC events. Invasive BCs occurring within 15 years after benign biopsy were classified as ER+ if ER staining was &amp;gt;1%. BC case-only associations with ER status were evaluated using multivariate logistic regression. Full-cohort hazard ratios (HR) and 95% confidence intervals (CI) for risk of ER-specific subtypes were estimated using Cox proportion hazards regression. Results: Among 13,410 women undergoing a benign breast biopsy from 1967-2001, 656 invasive BCs (459 ER+, 106 ER, 106 unknown) occurred within 15 years. Women who developed ER+ and ER- BCs were similar in age at the time of their prior benign breast biopsy (p=0.34). Although benign biopsies in women who later developed ER+ BC were more likely to show complete involution (23% vs 15% for ER- BC), this was not statistically significant (p=0.06). However, the degree of epithelial proliferation was significantly associated with ER status of later BCs (p=0.001), with ER+ BCs more likely than ER- BCs to have had a prior biopsy with atypical hyperplasia (16% vs 8%), and ER+ BCs less likely than ER- BCs to have had a prior biopsy with proliferative disease without atypia (33% vs 52%); this association remained after multivariate adjustment (p=0.003). We further pursued the association of epithelial proliferation with differential risk of ER+ and ER- BC in our overall cohort of 13,410 women (Table 1). Compared to women with non-proliferative disease, women with proliferative disease +/- atypia had ∼2-fold hazard ratios for ER- BC, whereas hazard ratios for ER+ BC were higher in women with atypical hyperplasia (∼4-fold) compared to proliferative disease. Hazard Ratio of ER+ and ER- BC within 15 years of BBD based upon degree of epithelial proliferation at benign biopsyCancer TypeGroupNN EventsHazard Ratio (95% CI)p-valueInvasive ER- ≤15 yearsNP8478421.00 (ref)&amp;lt;0.0001 PD4229542.63 (1.76, 3.93) AH70382.60 (1.22, 5.54) Invasive ER+ ≤15 yearsNP84782321.00 (ref)&amp;lt;0.0001 PD42291511.33 (1.09, 1.64) AH703744.41 (3.39, 5.73) NP=nonproliferative disease, PD=proliferative disease without atypia; AH=atypical hyperplasia Conclusion: ER+ and ER- breast cancers appear to have different features on prior benign breast biopsy, with atypical hyperplasia showing increased risk for both types of breast cancer, but a greater risk for ER+ tumors. Citation Format: Amy C Degnim, Derek C Radisky, Robert A Vierkant, Ryan D Frank, Marlene H Frost, Vernon S Pankratz, Celine M Vachon, Tanya L Hoskin, Julie M Cunningham, Chen Wang, Jean-Pierre Kocher, Teresa M Allers, Joanne L Johnson, Tina J Hieken, Karthik Ghosh, Lynn C Hartmann, Daniel W Visscher. Histologic features of benign breast biopsy tissue and association with ER positive and ER negative breast cancer in the Mayo BBD cohort study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-06.

Abstract P4-14-06: Characteristics of benign breast disease and subsequent risk of breast cancer differ by age among African Americans

Abstract Introduction: A history of benign breast disease (BBD) is common and certain established pathologic features are associated with increased breast cancer risk. These associations have been reported primarily from studies of white women, where incidence of BBD peaks in the 4th or 5th decade of life. Previous work in an African American (AA) cohort of women with BBD showed AA women were younger at their first BBD diagnosis. Thus investigating whether different features of benign lesions may be associated with age and/or subsequent breast cancer risk in this population is warranted. Methods: Benign breast biopsies from 1,867 AA women with BBD diagnosed from 1997-2003 were microscopically reviewed for 15 benign features (apocrine metaplasia (AM), ductal hyperplasia (DH), atypical ductal hyperplasia (ADH), lobular hyperplasia (LH), calcifications (Calc), cysts, duct ectasisa (DE), fibroadenoma (FA), fibrosis, intraductal papilloma (IDP), radial scar (RS), sclerosing adenosis (SA), columnar cell alterations (CC), mucocele-like tumors (MLT), and atropy), and followed for subsequent breast cancer in metropolitan Detroit, Michigan. Data from 439 women under 40 and 1,428 women 40 and older at BBD diagnosis were available for analysis, with a mean follow-up time of 14 years. Differences between age categories for BBD features were compared using chi-square tests, and risk of breast cancer was estimated with odds ratios (OR) and 95% confidence intervals (95% CI) calculated from logistic regression analysis. Results: Women 40 and over were more likely to be diagnosed with nearly all of the benign characteristics compared to younger women, including: AM, DH, Calc, cysts, CC, and ADH (all p-values &amp;lt;0.001). Younger women were more likely to present with FA (56% to 43%, p-value&amp;lt;0.001) and no atrophy (44% versus 24%, p-value&amp;lt;0.001) compared to older women. Risk of subsequent breast cancer was associated with cysts (OR=3.95, 95% CI: 1.09, 14.29) in the younger age group, but not the older (OR=1.25, 95% CI: 0.76, 2.03). CC were also associated with breast cancer risk in the young (OR=5.35, 95% CI: 1.45, 19.73) but not the older women (OR=1.44, 95% CI: 0.82, 2.50). RS were associated with increased risk in both groups, but only statistically significant for the older women (OR=3.60, 95% CI: 1.54, 8.39), and not the younger women (OR=6.64, (95% CI: 0.73, 60.67). Similarly, risk of cancer was associated with a diagnosis of ADH in both groups, but only statistically significant among older women (OR=3.02, 95% CI: 1.34, 6.79), and not younger women (OR=6.75, 95% CI: 0.71, 64.43). Conclusions: Characteristics of BBD differ by age, with more women over the age of 40 being diagnosed with various conditions. Risk of subsequent cancer also varies, although RS, CC and ADH appear to increase risk in both age groups. Citation Format: Michele L Cote, Julie J Ruterbusch, Sudeshna Bandyopadhyay, Quratulain Ahmed, Barra Alosh, Eman Abdulfatah, Haitham Arabi, Rouba Lynn Ali-Fehmi. Characteristics of benign breast disease and subsequent risk of breast cancer differ by age among African Americans [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-14-06.

Breast cancer risk associated with benign breast disease: systematic review and meta-analysis.

Benign breast disease (BBD) is a broad category of diagnoses reported to convey a variable degree of increased risk of developing breast cancer. A meta-analysis of the existing literature was performed to quantify the risk estimate associated with BBD. Pubmed, Google Scholar, and EMBASE databases were searched in January 2011. English retrospective and prospective observational studies published from 1972 to 2010 evaluating BBD and the risk of breast cancer were included with data acquisition reported from 1930 to 2007. Eligibility was performed independently following a standardized protocol for full-text publication review by a single reviewer and reviewed by a second author. Of the 3,409 articles retrieved from the literature search, 32 studies met the selection criteria. Reported risk estimates, including relative risk, odds ratio, standardized incidence ratios, rate ratio, hazards ratio, and incidence rate ratio, were the primary outcomes extracted. The most commonly reported pathologies were decided prior to extraction and organized into the following categories for analysis of the extracted risk estimate: non-proliferative disease (NPD), proliferative disease without atypia, benign breast disease not otherwise specified (BBD), and atypical hyperplasia not otherwise specified (AHNOS). The mean age at benign breast biopsy was 46.1 years and the mean age of developing breast cancer was 55.9 years. The mean follow-up length was 12.8 years (range 3.3-20.6). The summary risk estimate of developing breast cancer for NPD was 1.17 (N = 8; 95% CI 0.94-1.47). Proliferative disease without atypia was associated with significantly increased risk of future breast cancer, summary relative risk 1.76 (N = 15; 95% CI 1.58-1.95). The summary risk estimate for AHNOS was 3.93 (N = 13; 95% CI 3.24-4.76). This meta-analysis demonstrates that proliferative benign breast disease with or without atypia is associated with a significant increase in risk of developing breast cancer. These data support management strategies for women with benign breast disease such as additional screening methods or chemoprevention.

Model for individualized prediction of breast cancer risk after a benign breast biopsy.

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). 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. 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). 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 woman's breast cancer risk after a benign biopsy than the BCRAT.

Atypical Hyperplasia of the Breast: Common, Important, and Not Adequately Recognized

Of the approximately one million benign breast biopsies performed annually in U.S. women, some 10% yield a diagnosis of atypical hyperplasia (AH, histologically classified as ductal or lobular). AH is associated with a 25-year cumulative risk for breast cancer approaching 30%. In a special report, experts make several points about AH:

Early Human Papilloma Virus (HPV) Oncogenic Influences in Breast Cancer.

BACKGROUNDHuman papilloma viruses (HPVs) may act early in breast oncogenesis (“hit-and-run” phenomena).METHODSThe authors used immunohistochemistry for the identification of HPV E7 oncogenic protein expression in 32 sets of benign and subsequent breast cancer specimens from the same Australian patients.RESULTSHPV E7 oncoprotein was clearly expressed in the nuclei of 23 (72%) of the 32 benign specimens and 20 (62.5%) of the subsequent 32 breast cancer specimens in the same patients. There was no HPV E7 protein expression in seven (30%) of the 23 breast cancer specimens that had prior HPV E7 protein-positive benign breast biopsies in the same patients.CONCLUSIONSThis observation suggests that HPV oncogenic influences occur early in some breast cancers. This finding confirms the previous observations. This early influence of HPVs may be the reason why there is no increase in the prevalence of HPV-associated breast cancer in immunocompromised patients as compared to HPV-associated cervical cancer.

Short-term imaging follow-up of patients with concordant benign breast core needle biopsies: is it really worth it?

Women with histologically proven concordant benign breast disease are often followed closely after biopsy for a period of two years, and they are considered to be at high-risk for cancer development. Our goal was to evaluate the utility of short-term (six-month) imaging follow-up and determine the incidence of breast cancer development in this population. Retrospective review of concordant benign breast pathology was performed in 558 patients who underwent multimodality breast core biopsy. A total of 339 patients (60.7%) with 393 biopsies qualified for the study. The six-, 12-, and 24-month incidence rates of breast cancer development were estimated with 95% confidence intervals (CI), using the exact method binomial proportions. No cancer was detected in 285 of 339 patients (84.1%) returning for the six-month follow-up. No cancer was detected in 271 of 339 patients (79.9%) returning for the 12-month follow-up. Among 207 follow-up exams (61.1%) performed at 24 months, three patients were detected to have cancer in the ipsilateral breast (1.45% [95% CI, 0.30%-4.18%]) and two patients were detected to have cancer in the contralateral breast (0.97% [95% CI, 0.12%-3.45%]). Subsequent patient biopsy rate was 30 of 339 (8.85%, [95% CI, 6.05%-12.39%]). Three ipsilateral biopsies occurred as a sole result of the six-month follow-up of 285 patients (1.05%, [95% CI, 0.22%-3.05%]). Short-term imaging follow-up did not contribute to improved breast cancer detection, as all subsequent cancers were detected on annual mammography. Annual diagnostic mammography after benign breast biopsy may be sufficient.

Capsule commentary on Schonberg et al., Older women's experience with a benign breast biopsy—a mixed methods study.

Women 65 years and older are commonly screened for breast cancer with mammography. Models estimate that screening 1,000 women biannually for 10 years after the age of 69 would result in two fewer cancer deaths, 200 false positive mammograms, and 13 cases of over-diagnosis (breast cancer that would not have been clinically evident otherwise).1 The study by Schonberg et al. evaluates the effects of benign breast biopsies upon older women, using validated scales of psychological and physical consequences measured at the time of biopsy and after 6 months, and uses qualitative data to develop a conceptual model of undergoing a benign breast biopsy.2 At the time of biopsy, 76 % of women reported negative psychological consequences, which persisted at 6 months for 39 %. After 6 months, one in five women felt that worry interfered with their daily activities, and there was a trend for women with ≤ 9 years life expectancy to have higher negative psychological consequences compared to healthier women. Women also noted competing health issues in the qualitative data, all of which support the need for personalized decision making to balance risks and benefits of breast cancer screening in this age group. Opportunities identified for optimizing the experience of breast biopsies for women include positive interactions with radiology staff and physicians and systematic processes that minimize the wait time for test results. Women want information that explains biopsy procedures and diagnosis-specific information post-biopsy. Patient education materials would need to reflect current recommendations,3 particularly for diagnoses that are associated with higher risk for breast cancer, such as atypia, and to acknowledge the paucity of evidence supporting mortality benefit from such follow-up. Delivering this information via the primary care provider, with whom women wanted to communicate, would improve on-going shared decision making about future breast cancer screening. Decision aids that personalize screening recommendations based upon women’s competing medical issues and life expectancy4,5 would ideally be easily accessible in the primary care setting within an electronic medical record. These supports are needed to decrease the harms of breast cancer screening among women 65 years and older.

Older women's experience with a benign breast biopsy—a mixed methods study.

Little is known about older women's experience with a benign breast biopsy. To examine the psychological impact and experience of women ≥ 65 years of age with a benign breast biopsy. Prospective cohort study using quantitative and qualitative methods. Three Boston-based breast imaging centers. Ninety-four English-speaking women ≥ 65 years without dementia referred for breast biopsy as a result of an abnormal mammogram, not aware of their biopsy results at baseline, and with a subsequent negative biopsy. We interviewed women at the time of breast biopsy (before women knew their results) and 6 months post-biopsy. At both interviews, participants completed the validated negative psychological consequences of screening mammography questionnaire (PCQ, scores range from 0 to 36 [high distress], PCQ ≥ 1 suggests a psychological consequence, PCQs <1 are reported at time of screening) and women responded to open-ended questions about their experience. At follow-up, participants described the quality of information received after their benign breast biopsy. We used a linear mixed effects model to examine if PCQs declined over time. We also reviewed participants' open-ended comments for themes. Overall, 88% (83/94) of participants were non-Hispanic white and 33% (31/94) had a high-school degree or less. At biopsy, 76% (71/94) reported negative psychological consequences from their biopsy compared to 39% (37/94) at follow-up (p < 0.01). In open-ended comments, participants noted the anxiety (29%, 27/94) and discomfort (28%, 26/94) experienced at biopsy (especially from positioning on the biopsy table). Participants requested more information to prepare for a biopsy and to interpret their negative results. Forty-four percent (39/89) reported at least a little anxiety about future mammograms. The high psychological burden of a benign breast biopsy among older women significantly diminishes with time but does not completely resolve. To reduce this burden, older women need more information about undergoing a breast biopsy.

Results following a benign breast biopsy – A breast care nurse led “virtual” telephone clinic

Introduction: A percentage of core biopsies are performed in the one stop clinic knowing the histology will almost definitely be benign. As this accounts for up to 16% of lesions sampled in our centre, we wanted to relieve capacity in clinic, improve the patient pathway and reduce patient waiting times by introducing a telephone results clinic for benign results. We report on our 6 month experience of this new “virtual” clinic.

Short interval follow-up after a benign concordant MR-guided vacuum assisted breast biopsy – is it worthwhile?

To determine the utility of short-interval follow-up after benign concordant MRI-guided breast biopsy. Institutional review board approved, retrospective review of consecutive biopsies performed over 3 years (2007-10) yielded 170 women with 188 lesions that were considered benign concordant. Indication for original study, biopsy results, follow-up recommendations, compliance and outcomes of subsequent MRI and mammography examinations were reviewed. The most common indication for breast MRI was high-risk screening 119/170 (70 %). Overall, 59 % of lesions (113/188) had follow-up MRI. Of those lesions (n = 113), 43 % (49/113) presented within 7 months, 26 % (29/113) presented within 8-13 months, 11.5 % (13/113) presented within 14-22 months, and 19 % (22/113) presented after 23 months. At initial follow-up, 37 % of lesions were stable and 61 % were decreased in size. Three lesions were recommended for excision based on follow-up imaging with one malignancy diagnosed 2 years following biopsy. One additional patient had MRI-detected bilateral cancers remote from the biopsy site 3 years after biopsy. Overall cancer yield of lesions with follow-up MRI was 0.9 % (1/113); no cancers were detected at 6 months. Our data suggests that 6-month follow-up may not be required and that annual screening MRI would be acceptable to maintain a reasonable cancer detection rate. Follow-up recommendations after benign concordant MRI-guided breast biopsy remain controversial. Cancer detection rate was 0.9 % overall with no cancers detected at 6 months. Short-interval follow-up after benign concordant MRI-guided breast biopsy may not be necessary.