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Many germline mutations have been implicated in breast cancer pathogenesis and despite several studies on occult atypical lesions in prophylactic mastectomy specimens from patients with BRCA1/2 mutations, there are very limited data on other genes associated with increased breast cancer risk and the distribution of lesions in patients with hereditary breast cancer. We identified 207 patients who underwent bilateral prophylactic mastectomy due to germline mutations in BRCA1/2, PALB2, CHEK2, ATM, CDH1, PTEN, BARD1, or strong family history between 2015 and 2023. Patients with biopsy-proven past or current invasive breast carcinoma or carcinoma in-situ preoperatively were excluded. In addition to multiple benign lesions, the following atypical lesions were identified: flat epithelial atypia (16.9%), atypical ductal hyperplasia (14.0%), lobular neoplasia (14.0%), ductal carcinoma in-situ (4.3%), invasive ductal carcinoma (0.4%). Both low-grade and high-grade pathway lesions were identified in this cohort, and in a subset of patients, they co-occurred. The frequency of atypical lesions identified in patients with strong family history were comparable to those with proven germline mutation. PTEN immunohistochemistry showed loss of expression in ductal carcinoma in-situ and tubular adenomas in PTEN-mutant patients. Overall, findings from this cohort support the benefit of prophylactic mastectomy in patients with germline mutations and/or strong family history. Additionally, this is the first demonstration that PTEN immunohistochemistry may be helpful in identifying germline mutations in patients with atypical or neoplastic proliferations., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Research findings remain inconsistent whether caffeine consumption is associated with invasive breast cancer. We aimed to examine the association between caffeine intake from coffee and tea and incident invasive breast cancer among postmenopausal women. We included 79 871 participants in the Women's Health Initiative Observational Study in the current analysis. Incident invasive breast cancers were identified through September 30, 2015. Caffeine intake (mg/day) from caffeinated and decaffeinated coffee and tea was estimated based on self-reported frequency (cups/day) and average caffeine amount in each beverage. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analyses were conducted to explore whether associations of caffeine intake from coffee and tea with invasive breast cancer were different by age, race and ethnicity, smoking status, body mass index, history of hormone therapy use, alcohol intake and subtypes of breast cancer. During a median follow-up of 16.0 years, 4719 incident invasive breast cancers were identified. No significant association was found between caffeine intake from coffee and tea and invasive breast cancer incidence after adjusting for demographic, lifestyle and reproductive factors: HRs (95% CIs) for increasing quartiles of caffeine intake compared to the lowest were 1.03 (0.94, 1.12), 1.04 (0.95, 1.13) and 1.03 (0.94, 1.13), respectively (P-for-trend = .54). No significant associations of coffee and tea intake (cups/day) with overall breast cancer risk were found. Our findings are consistent with others showing no clear association of caffeine consumption with invasive breast cancer among postmenopausal women., (© 2021 UICC.)

Ductal carcinoma in situ (DCIS), which accounts for one out of every five new breast cancer diagnoses, will progress to potentially lethal invasive ductal carcinoma (IDC) in about 50% of cases. Vitamin D compounds have been shown to inhibit progression to IDC in the MCF10DCIS model. This inhibition appears to involve a reduction in the cancer stem cell-like population in MCF10DCIS tumors. To identify genes that are involved in the vitamin D effects, a global transcriptomic analysis was undertaken of MCF10DCIS cells grown in mammosphere cultures, in which cancer stem-like cells grow preferentially and produce colonies by self-renewal and maturation, in the presence and absence of 1α25(OH) 2 D 3 and a vitamin D analog, BXL0124. Using next-generation RNA-sequencing, we found that vitamin D compounds downregulated genes involved in maintenance of breast cancer stem-like cells (e.g., GDF15 ), epithelial-mesenchymal transition, invasion, and metastasis (e.g., LCN2 and S100A4 ), and chemoresistance (e.g., NGFR, PPP1R1B , and AGR2 ), while upregulating genes associated with a basal-like phenotype (e.g., KRT6A and KRT5 ) and negative regulators of breast tumorigenesis (e.g., EMP1 ). Gene methylation status was analyzed to determine whether the changes in expression induced by vitamin D compounds occurred via this mechanism. Ingenuity pathway analysis was performed to identify upstream regulators and downstream signaling pathway genes differentially regulated by vitamin D, including TP63 and vitamin D receptor -mediated canonical pathways in particular. This study provides a global profiling of changes in the gene signature of DCIS regulated by vitamin D compounds and possible targets for chemoprevention of DCIS progression to IDC in patients., (©2020 American Association for Cancer Research.)

Purpose: The Prosigna-PAM50 risk of recurrence (ROR) score has documented clinical utility for the prediction of 10-year distant recurrence (DR). The present study investigated the value of Prosigna-PAM50 for predicting 10-year DR and overall survival after 5 years of endocrine treatment for postmenopausal patients with invasive lobular carcinoma., Patients and Methods: Using the Danish Breast Cancer Group database, we identified patients with a diagnosis from 2000 to 2003 of estrogen receptor-positive, human epidermal growth factor receptor 2-negative invasive ductal (n = 1570) or lobular (n = 341) cancer > 20 mm or 1 to 3 positive lymph nodes and applied multivariate Cox models., Results: The median follow-up for DR was 9.3 years and for overall survival 15.2 years. Of the 341 lobular and 1570 ductal cases, 140 (41%) and 349 (22%) were classified as low ROR, with a 10-year DR rate of 7.7% (95% confidence interval [CI], 3.7%-13.6%) and 3.5% (95% CI, 1.8%-6.2%), respectively. The 10-year DR rate for the intermediate ROR group for those with lobular cancer was 18% (95% CI, 10.1%-27.9%) compared with 9.7% (95% CI, 6.7%-13.4%) for those with ductal cancer. Luminal B tumors had a significantly worse outcome than luminal A tumors in both lobular (hazard ratio, 1.89; 95% CI, 1.03%-3.45%; P = .04) and ductal (hazard ratio, 3.18; 95% CI, 2.29%-4.43%; P < .0001) cancer., Conclusion: Prosigna PAM-50 provides significant prognostic information beyond the clinicopathologic factors in patients with invasive lobular breast cancer. Those with lobular cancer had worse 10-year DR rates compared with those with ductal cancer in the same ROR category. Our results could have an effect on the treatment decisions regarding the addition of chemotherapy for those in the intermediate ROR group., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Histopathologic grade provides an integrated measure of biologic features which affects cancer prognosis. In invasive ductal breast cancer (IDBC), the grade of the ductal carcinoma in situ (DCIS) and invasive components are usually concordant, suggesting grade is established early in tumorigenesis and may be linked to etiologic factors. In this study, we used prospectively collected data from postmenopausal women in the Cancer Prevention Study-II (CPS-II) Nutrition Cohort to compare risk factor associations among low-grade and high-grade DCIS, as well as low-grade and high-grade IDBC., Methods: Among 73,825 cancer-free women at enrollment in the CPS-II Nutrition Cohort in 1992-1993 (mean age: 62.1 years), we verified 802 diagnosed with DCIS (C50 8500/2; n = 430 low-grade and 372 high-grade) and 3,125 with IDBC (C50 8500/3; n = 2,221 low-grade and 904 high-grade) through June 2013. Person-time contribution was conditional on screening mammograms self-reported on biennial surveys. Multivariable-adjusted joint Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI)., Results: A personal history of benign breast disease was more strongly associated with higher risk of low-grade DCIS (HR = 2.20, 95% CI 1.81-2.67; p for heterogeneity = 0.0004) than high-grade DCIS. Consumption of two or more alcoholic drinks/day was only associated with a higher risk of low-grade IDBC (HR = 1.58, 95% CI 1.33-1.88; p for heterogeneity = 0.005)., Conclusions: These results suggest heterogeneity by grade for breast cancer etiology. Identification of potential risk factor differences among low-grade and high-grade DCIS and IDBC may help to clarify associations, and ultimately, improve breast cancer risk prediction models.

Background: Increased use of contralateral prophylactic mastectomy (CPM) as treatment for ductal carcinoma in situ (DCIS) in the US was first noted in the early 2000s. Optimization of treatment guidelines for DCIS requires an understanding of current surgical treatment trends, particularly as they may differ by patient sociodemographic and community resource factors., Objective: The aim of this study was to evaluate surgical treatment trends among US women with DCIS and to assess the impact of sociodemographic and community resource factors on surgical treatment choice., Methods: The Surveillance, Epidemiology, and End Results dataset was queried for women aged 40 years and older who were diagnosed with unilateral DCIS between 2000 and 2014. Annual mastectomy rates were compared over time by age and race/ethnicity. Multivariable logistic regressions were performed to identify predictors of mastectomy use, with patient sociodemographics, tumor characteristics, and community resource factors (i.e. plastic surgeon density) as covariates., Results: A total of 130,731 women with DCIS met the inclusion criteria. Overall mastectomy rates remained relatively unchanged over the study period (25-30%). CPM use increased for all age and race/ethnic groups, with the greatest increase exhibited by women aged 40-49 years [relative to 2000; 2014 odds ratio (OR) 10.6]. With respect to community resource factors, CPM use, as opposed to unilateral mastectomy, was associated with counties of higher education level (OR 1.52), higher income level (OR 1.22), and lower plastic surgeon density (OR 1.26)., Conclusion and Relevance: While the popularity of mastectomy in the management of DCIS has remained relatively unchanged since the turn of the century, the use of CPM has risen substantially. Younger women with DCIS have seen the greatest increase in CPM use, a choice that remains influenced by race/ethnicity as well as income, education, and health resource availability. Until clinical risk stratifiers of DCIS are identified, the surgical decision-making paradigm must be improved so that treatment choice remains sensitive to cultural differences but becomes independent of income, education, and health resource availability.

Background Digital breast tomosynthesis (DBT) is replacing digital mammography (DM) in the clinical workflow. Currently, there are limited prospective studies comparing the diagnostic accuracy of both examinations and the role of synthetic mammography (SM) and computer-aided detection (CAD). Purpose To compare the accuracy of DM versus DM + DBT in population-based breast cancer screening. Materials and Methods This prospective study, performed from November 2010 to December 2012, included 24 301 women (mean age, 59.1 years ± 5.7 [standard deviation]) with 281 cancers, of which 51 were interval cancers. Each examination was independently interpreted with four reading modes: DM, DM + CAD, DM + DBT, and SM + DBT. Sensitivity and specificity were compared for DM versus DM + DBT, DM versus DM + CAD, DM + DBT versus SM + DBT, and DM versus DM + DBT at double reading. Reader-adjusted performance characteristics of reading modes were evaluated on the basis of pre-arbitration (initial interpretation) scores. Statistical analysis was based on cluster bootstrap analysis using 10 000 random resamples. Results Sensitivity was 54.1% (152 of 281) for DM and 70.5% (198 of 281) for DM + DBT. Reader-adjusted difference was 12.6% (95% confidence interval [CI]: 5.2%, 19.7%; P = .001). Specificity was 94.2% (false-positive fraction [FPF], 5.8%; 1388 of 24 020) for DM and 95.0% (FPF, 5.0%; 1209/24 020) for DM + DBT, with a reader-adjusted difference in FPF of -1.2% (95% CI: -1.7%, -0.7%; P < .001). Sensitivity was 69.0% (194 of 281) for SM + DBT and 70.5% (198 of 281) for DM + DBT, with a reader-adjusted difference of 1.0% (95% CI: -6.2%, 8.5%; P = .77). Specificity was 95.4% (FPF, 4.6%; 1111 of 24 020) for SM + DBT and 95.0% (FPF, 5.0%;1209 of 24 020) for DM + DBT, with reader-adjusted 95% CIs for FPF of 4.7%, 5.4% and 5.0%, 5.7%, respectively, and a difference of -0.3% (95% CI: -0.8%, 0.2%; P = .23). Differences in sensitivity and specificity with the addition of CAD were small and not significant (P > .2). Conclusion Addition of digital breast tomosynthesis to digital mammography resulted in significant gains in sensitivity and specificity. Synthetic mammography in combination with digital breast tomosynthesis had similar sensitivity and specificity to digital mammography in combination with digital breast tomosynthesis. © RSNA, 2019 See also the editorial by Lång in this issue.

Background: Initially performed only in prophylactic cases, indications for nipple-sparing mastectomy have expanded. Trends and surgical outcomes stratified by nipple-sparing mastectomy indication have not yet been fully examined., Methods: Demographics and outcomes for all nipple-sparing mastectomies performed from 2006 to 2017 were compared by mastectomy indication., Results: A total of 1212 nipple-sparing mastectomies were performed: 496 (40.9 percent) for therapeutic and 716 (59.1 percent) for prophylactic indications. Follow-up time was similar between both the therapeutic and prophylactic nipple-sparing mastectomy groups (47.35 versus 46.83 months, respectively; p = 0.7942). Therapeutic nipple-sparing mastectomies experienced significantly greater rates of major (p = 0.0165) and minor (p = 0.0421) infection, implant loss (p = 0.0098), reconstructive failure (p = 0.0058), and seroma (p = 0.0043). Rates of major (p = 0.4461) and minor (p = 0.2673) mastectomy flap necrosis and complete (p = 0.3445) and partial (p = 0.7120) nipple necrosis were equivalent. The overall rate of locoregional recurrence/occurrence per nipple-sparing mastectomy was 0.9 percent: 2.0 percent in therapeutic nipple-sparing mastectomies and 0.1 percent in prophylactic nipple-sparing mastectomies (p < 0.0001)., Conclusions: Approximately 40 percent of nipple-sparing mastectomies are currently performed for therapeutic indications. Therapeutic nipple-sparing mastectomies had higher rates of infectious complications and reconstructive failure. Rates of locoregional cancer recurrence/occurrence are low, but occur significantly more often after therapeutic nipple-sparing mastectomy., Clinical Question/level of Evidence: Therapeutic, III.

Purpose: Chlorella vulgaris (CV) has exhibited immune-enhancing and protective activities against cancer and infections. However, there is an increasing concern about the use of Chlorella species in human, regarding its various molecules with antigenic features found in infectious microorganisms. Our goal was to investigate the impact of higher concentrations of CV on tumor growth in spontaneous mouse mammary tumor (SMMT) models., Methods: Balb/c mice were daily given CV powder at doses of 0, 200, or 300 mg/kg for 42 days (CONTROL, CV200, and CV300 groups, respectively; n = 6/group). On day 14, the SMMT was inoculated. Tumor volume (TV) and body weight (BW) were monitored on 5-day intervals following tumor challenge. On day 43, blood, spleen, lungs, and tumor tissues were collected. Histopathological examinations on lungs and tumor tissues were performed following hematoxylin-eosin staining. Intratumor expression of 27 genes was assessed by real-time PCR. Total IgG, IFNγ, and IL-4 levels in serum and spleen culture supernatant were measured by ELISA., Results: The TV/BW index showed significant increase in the CV200 group compared to the CONTROL (p = 0.047). The CV200 tumors exhibited more malignant phenotype, higher angiogenesis rate, and lower peritumoral neutrophil and macrophage-to-lymphocyte infiltration ratio compared to the CONTROL. Serum concentrations of IFNγ, IL-4, and IgG were declined, and the spleen IFNγ and IgG production was higher in the CV200 compared to the CONTROL. The IL-1β, IL-10, TGFβ1, FOXP3, HO-1, Gr1, CD11b, PCNA, LCN2, iNOS2, VEGFR2, CD31, and CD105L expressions were markedly increased in the CV200 tumors compared to the CONTROL (p = 0.001, 0.002, 0.006, 0.021, 0.004, 0.030, 0.016, 0.031, 0.025, 0.008, 0.014, 0.022, and 0.037, respectively). The changes in cytokine, IgG and gene expression values considerably correlated with tumor size, as well as with each other., Conclusions: Our data provided evidence that C. vulgaris at a specific dose (200 mg/kg) promoted tumor growth in a mammary tumor model. This consequence might reflect an immune derangement in favor of developing a protumor microenvironment. However, this hypothesis needs to be further investigated in future.

Purpose To compare detection rates of ductal carcinoma in situ (DCIS), classified according to nuclear grade, between the prevalence round (baseline screening) and two subsequent screening rounds of a population-based digital mammography screening program, to assess differences over time. Materials and Methods The cancer registry provided data for 1970 graded pure DCIS cases from 16 screening regions of the prevalence round (baseline screening, from 2005 to 2008), first subsequent round, and second subsequent round; the interval between all screening rounds was 22-30 months. Age-adjusted logistic regression analysis was performed to compare the grade-specific detection rates between the prevalence round (reference) and subsequent screening rounds. Results Over all screening rounds, cancer detection rates were lowest for low-grade DCIS (range, 0.11 [58 of 508 817 patients] to 0.25 [178 of 713 867 patients] per 1000 women screened) and highest for high-grade DCIS (range, 0.53[271 of 508 817 patients] to 0.59 [237 of 398 944 patients] per 1000 women screened). Detection rates for low-grade DCIS were significantly lower in the first (odds ratio [OR] = 0.45, P < .001) and second (OR = 0.57, P < .001) subsequent screening rounds compared with that in the prevalence round; the relative reduction of detection rates of intermediate-grade DCIS was less pronounced (OR = 0.79, P = .006 and OR = 0.76, P = .003, respectively). Conversely, the detection rate of high-grade DCIS remained at the high level found in the prevalence screening (OR = 0.89, P = .143 and OR = 0.97, P = .700, respectively). Conclusion The findings demonstrate persistently high detection rates of high-grade DCIS in two consecutive subsequent screening rounds compared with the prevalence round; conversely, rates of low-grade DCIS and, less markedly, intermediate-grade DCIS decreased in subsequent rounds. Grade-related changes of DCIS detection are suggestive of distinct dynamics of lesion progression. © RSNA, 2017 An earlier incorrect version of this article appeared online. This article was corrected on November 10, 2017.

Background: The optimal duration of extended endocrine therapy beyond five years after initial aromatase inhibitor-based adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer is still unknown. Therefore, we conducted a clinical trial to compare two different extended endocrine therapy durations., Methods: In the randomized phase III IDEAL trial, postmenopausal patients with hormone receptor-positive breast cancer were randomly allocated to either 2.5 or five years of letrozole after the initial five years of any endocrine therapy. The primary end point was disease free survival (DFS), and secondary end points were overall survival (OS), distant metastasis-free interval (DMFi), new primary breast cancer, and safety. Hazard ratios (HRs) were determined using Cox regression analysis. All analyses were by intention-to-treat principle., Results: A total of 1824 patients were assigned to either 2.5 years (n = 909) or five years (n = 915) of letrozole, with a median follow-up of 6.6 years. A DFS event occurred in 152 patients in the five-year group, compared with 163 patients in the 2.5-year group (HR = 0.92, 95% confidence interval [CI] = 0.74 to 1.16). OS (HR = 1.04, 95% CI = 0.78 to 1.38) and DMFi (HR = 1.06, 95% CI = 0.78 to 1.45) were not different between both groups. A reduction in occurrence of second primary breast cancer was observed with five years of treatment (HR = 0.39, 95% CI = 0.19 to 0.81). Subgroup analysis did not identify patients who benefit from five-year extended therapy., Conclusion: This study showed no superiority of five years over 2.5 years of extended adjuvant letrozole after an initial five years of adjuvant endocrine therapy., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Risk communication surrounding the prevention of invasive breast cancer entails not only understanding of the disease, risks and opportunities for intervention. But it also requires understanding and implementation of optimal strategies for communication with patients who are making these decisions. In this article, available evidence for the issues surrounding risk communication and decision making in the prevention of invasive breast cancer are reviewed and strategies for improvement are discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Developments in breast cancer treatment have resulted in reduction in breast cancer mortality in the developed world. However incidence continues to rise and greater use of preventive interventions including the use of therapeutic agents is needed to control this burden. High quality evidence from 9 major trials involving more than 83000 participants shows that selective oestrogen receptor modulators (SERMs) reduce breast cancer incidence by 38%. Combined results from 2 large trials with 8424 participants show that aromatase inhibitors (AIs) reduce breast cancer incidence by 53%. These benefits are restricted to prevention of ER positive breast cancers. Restricting preventive therapy to high-risk women improves the benefit-harm balance and many guidelines now encourage healthcare professionals to discuss preventive therapy in these women. Further research is needed to improve our risk-prediction models for the identification of high risk women for preventive therapy with greater accuracy and to develop surrogate biomarkers of response. Long-term follow-up of the IBIS-I trial has provided valuable insights into the durability of benefits from preventive therapy, and underscores the need for such follow up to fully evaluate other agents. Full utilisation of preventive therapy also requires greater knowledge and awareness among both doctors and patients about benefits, harms and risk factors. Healthcare professionals should routinely discuss preventive therapy with women at high-risk of breast cancer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Potential benefits of screening need to be carefully balanced against the financial burden for the national health care system., Objectives: To assess the cost-effectiveness of population-based mammographic screening in the 3-million region of Lower Silesia (Poland) after initial and 3 subsequent rounds., Material and Methods: Data was collected in a prospective manner using the databases of the official computer system for the monitoring of prophylaxis programs (SIMP), National Health Fund (Lower Silesia Regional Branch) and the Lower Silesia Cancer Registry. The expenses from each analyzed year were obtained from the Regional Coordinating Center for Screening Programs. The number of screen-detected and pathologically proven invasive and ductal in situ cancers was calculated. Costs of cancer detection were measured, converted into US dollars (USD), and expressed in 2015 USD using the comparison of purchasing power of money calculated with the Consumer Price Index., Results: The total expense for the screening program in the initial round (2007-2008), first (2009-2010), second (2011-2012) and third (2013-2014) subsequent rounds was 4 732 383, 6 043 509, 6 484 834, and 5 900 793 USD whereas the number of cancer detected was 1049, 987, 1312, and 1070. The costeffectiveness ratio obtained in the program for each year was 4511, 6123, 4943, and 5515 USD per cancer found. The average cost of breast cancer detection in screening program in the region of Lower Silesia in years 2007-2014 was 5243 USD., Conclusions: The low cost of breast cancer detection in mammographic screening program makes it applicable for the health care systems in emerging economies.

Mouse Mammary Tumor Virus (MMTV) causes mammary carcinoma or lymphoma in mice. An increasing body of evidence in recent years supports its involvement also in human sporadic breast cancer. It is thus of importance to develop new strategies to impair the development, growth and metastasis of MMTV-associated cancers. The signal peptide of the envelope precursor protein of this virus: MMTV-p14 (p14) is an excellent target for such strategies, due to unique characteristics distinct from its regular endoplasmic reticulum targeting function. These include cell surface expression in: murine cancer cells that harbor the virus, human breast cancer (MCF-7) cells that ectopically express p14, as well as cultured human cells derived from an invasive ductal breast carcinoma positive for MMTV sequences. These findings support its use in signal peptide-based immune targeting. Indeed, priming and boosting mice with p14 elicits a specific anti-signal peptide immune response sufficient for protective vaccination against MMTV-associated tumors. Furthermore, passive immunization using a combination of anti-p14 monoclonal antibodies or the transfer of T-cells from immunized mice (Adoptive Cell Transfer) is also therapeutically effective. With reports demonstrating involvement of MMTV in human breast cancer, we propose the immune-mediated targeting of p14 as a strategy for prevention, treatment and diagnosis of MMTV-associated cancers., Competing Interests: There is no conflict of interest.

Background: Rates of contralateral prophylactic mastectomy (CPM) have been increasing nationally. The goal of this study was to evaluate recent trends in rates of CPM and immediate breast reconstruction (IBR)., Methods: After institutional review board approval, we evaluated all surgical procedures for women with newly diagnosed unilateral stages 0-III breast cancer from January 2009 to December 2014. Patients opting for therapeutic mastectomy were classified as either unilateral mastectomy or bilateral mastectomy, if CPM was performed, and according to whether or not they underwent IBR. Analysis was performed using trend tests for univariate associations and both binary and multinomial logistic regression for multivariate analysis., Results: There were 3,195 women who underwent surgery for breast cancer--51% lumpectomy, 49% therapeutic mastectomy. Of the 1,571 patients undergoing therapeutic mastectomy, 829 (53%) underwent bilateral mastectomy. The rates of therapeutic mastectomy did not change over the study period (P = .92), but the use of IBR among patients undergoing therapeutic mastectomy increased from 37% in 2009 to 68% in 2014 (P < .0001). The use of bilateral mastectomy with IBR increased from 26% in 2009 to 46% in 2014 (P < .0001), whereas conversely the use of bilateral mastectomy without IBR decreased from 22% to 12% (P < .0001). IBR was associated with bilateral mastectomy; 69% of patients opting for IBR also underwent bilateral mastectomy compared with 38% choosing bilateral mastectomy in the group without IBR (adjusted odds ratio, 2.7; 95% CI, 2.1-3.5; P < .0001)., Conclusion: Over recent years, rates of bilateral mastectomy have remained high. The use of IBR increased substantially for women undergoing therapeutic mastectomy and women undergoing IBR were significantly more likely to opt for bilateral mastectomy. The availability of IBR may influence patients' decisions to pursue bilateral mastectomy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS., Methods: In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358., Results: Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6-8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 [95% CI 0·64-1·23]). The non-inferiority of anastrozole was established (upper 95% CI <1·25), but its superiority to tamoxifen was not (p=0·49). A total of 69 deaths were recorded (33 for anastrozole vs 36 for tamoxifen; HR 0·93 [95% CI 0·58-1·50], p=0·78), and no specific cause was more common in one group than the other. The number of women reporting any adverse event was similar between anastrozole (1323 women, 91%) and tamoxifen (1379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen., Conclusions: No clear efficacy differences were seen between the two treatments. Anastrozole offers another treatment option for postmenopausal women with hormone-receptor-positive DCIS, which may be be more appropriate for some women with contraindications for tamoxifen. Longer follow-up will be necessary to fully evaluate treatment differences., Funding: Cancer Research UK, National Health and Medical Research Council Australia, Breast Cancer Research Fund, AstraZeneca, Sanofi Aventis., (Copyright © 2016 Forbes et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Breast cancer prevention with pharmacologic agents requires that the breast be exposed to an effective drug; systemic exposure is unnecessary, and its harms lead many eligible women to decline preventive therapy. Local transdermal therapy (LTT) to the breast involves the application of active drugs to the breast skin, resulting in high concentrations in the breast but low systemic exposure. It is non-invasive, self-delivered, and not dependent on hepatic metabolism. Existing data on LTT include investigations demonstrating relief of mastalgia with topical 4-hydroxytamoxifen (4-OHT, an active tamoxifen metabolite). Two presurgical window trials in women with invasive breast cancer, and ductal carcinoma in situ (DCIS) demonstrate that LTT decreases proliferation of invasive and non-invasive cancer cells to a similar degree as oral tamoxifen, with low systemic levels, and no effect on coagulation proteins. These data are promising regarding the use of LTT for the primary prevention of breast cancer, and for therapy of DCIS, since systemic exposure is not required for either of these purposes. They also suggest that an LTT approach could be developed for any small, lipophilic molecule with good dermal permeation, thus greatly expanding the menu of drugs that could be tested for breast cancer prevention., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Despite their efficacy, uptake of selective estrogen receptor modulators for breast cancer chemoprevention remains low. Exemestane, an aromatase inhibitor, has recently been identified as a potential chemopreventive option with fewer serious side effects compared with selective estrogen receptor modulators in postmenopausal women. The purpose of this study was to assess the uptake of exemestane in a breast cancer prevention clinic. A retrospective chart review was conducted to capture chemoprevention uptake by postmenopausal women presenting to the Yale Breast Cancer Prevention Clinic between November 2011 and November 2012. Descriptive statistics of the study population have been presented. Statistical analyses were carried out using SAS 9.3 (SAS Institute Inc., Cary, North Carolina, USA) between December 2012 and February 2013. Of 90 postmenopausal women, 56 were eligible for chemoprevention. Their mean age was 56.8 years. Among the women, 39% had osteopenia or osteoporosis. Thirteen women chose to start chemoprevention medication (23%). Although 31% of the chemopreventive medication administered included exemestane, only four of 56 postmenopausal women opted for exemestane (7%). Chemoprevention uptake rates of postmenopausal women in the setting of a breast cancer prevention clinic are higher than that reported in the general population; however, they remain low overall despite the inclusion of exemestane as an option. A significant proportion of postmenopausal women have decreased bone density, which is a potential barrier to exemestane uptake. The results provide practical implications suggesting that exemestane may have limited impact on breast cancer chemoprevention uptake. Further investigations should focus on understanding the factors that influence, predict, and increase chemoprevention uptake.

Purpose: An increasing proportion of breast cancer patients undergo contralateral prophylactic mastectomy (CPM) to reduce their risk of contralateral breast cancer (CBC). Our goal was to evaluate CBC risk perception changes over time among breast cancer patients., Methods: We conducted a prospective, longitudinal study of women with newly diagnosed unilateral breast cancer. Patients completed a survey before and approximately 2 years after treatment. Survey questions used open-ended responses or 5-point Likert scale scoring (e.g., 5 = very likely, 1 = not at all likely)., Results: A total of 74 women completed the presurgical treatment survey, and 43 completed the postsurgical treatment survey. Baseline characteristics were not significantly different between responders and nonresponders of the follow-up survey. The mean estimated 10-year risk of CBC was 35.7 % on the presurgical treatment survey and 13.8 % on the postsurgical treatment survey (p < 0.001). The perceived risks of developing cancer in the same breast and elsewhere in the body significantly decreased between surveys. Both CPM and non-CPM (breast-conserving surgery or unilateral mastectomy) patients' perceived risk of CBC significantly decreased from pre- to postsurgical treatment surveys. Compared with non-CPM patients, CPM patients had a significantly lower perceived 10-year risk of CBC (5.8 vs. 17.3 %, p = 0.046) on postsurgical treatment surveys., Conclusions: The perceived risk of CBC significantly attenuated over time for both CPM and non-CPM patients. These data emphasize the importance of early physician counseling and improvement in patient education to provide women with accurate risk information before they make surgical treatment decisions.

Background: The rate of contralateral prophylactic mastectomy (CPM) for unilateral breast cancer has increased over the past decade, particularly for young women. This study investigates the impact of race and socioeconomic status (SES) on use of CPM., Study Design: Using the National Cancer Data Base (NCDB), we selected 1,781,409 stage 0 to II unilateral breast cancer patients between 1998 and 2011. Trends in use of CPM by race and SES were analyzed using chi-square tests and logistic regression models., Results: For women of all ages, rates of CPM increased, from 1.9% in 1998 to 10.2% in 2011 (p < 0.001), with higher rates in women ≤45 years old, rising from 3.7% in 1998 to 26.2% in 2011 (p < 0.001). Among young women, white women had the greatest increase in CPM from 4.3% in 1998 to 30.2% in 2011 (p < 0.001). In 2011, CPM rates were 30.2% for white, 18.5% for Hispanic, 16.5% for black, and 15.2% for Asian patients (p < 0.001). The gap in CPM use between white and minority patients persisted in every SES classification, geographic region, and facility type. On multivariate analysis, minority women were 50% less likely to undergo CPM than white women were., Conclusions: Young, white, breast cancer patients are twice as likely to undergo CPM compared with women in other racial groups, even after accounting for pathologic, patient, and facility factors. Variations in shared decision-making processes between women of different backgrounds may contribute to these trends, supporting the need for future studies investigating decision-making processes and decisional aids., (Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Concerns about breast cancer overdiagnosis have increased the need to understand how cancers detected through screening mammography differ from those first detected by a woman or her clinician. We investigated risk factor associations for invasive breast cancer by method of detection within a series of case-control studies (1992-2007) carried out in Wisconsin, Massachusetts, and New Hampshire (n=15,648 invasive breast cancer patients and 17,602 controls aged 40-79 years). Approximately half of case women reported that their cancer had been detected by mammographic screening and half that they or their clinician had detected it. In polytomous logistic regression models, parity and age at first birth were more strongly associated with risk of mammography-detected breast cancer than with risk of woman/clinician-detected breast cancer (P≤0.01; adjusted for mammography utilization). Among postmenopausal women, estrogen-progestin hormone use was predominantly associated with risk of woman/clinician-detected breast cancer (odds ratio (OR)=1.49, 95% confidence interval (CI): 1.29, 1.72), whereas obesity was predominantly associated with risk of mammography-detected breast cancer (OR=1.72, 95% CI: 1.54, 1.92). Among regularly screened premenopausal women, obesity was not associated with increased risk of mammography-detected breast cancer (OR=0.99, 95% CI: 0.83, 1.18), but it was associated with reduced risk of woman/clinician-detected breast cancer (OR=0.53, 95% CI: 0.43, 0.64). These findings indicate important differences in breast cancer risk factors according to method of detection., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In recent years, radical breast cancer surgery has been largely replaced by breast conservation treatment, due to early diagnosis and more effective adjuvant treatment. While breast conservation is mostly preferred, the trend of bilateral mastectomy has risen in the United States. The aim of this study is to determine factors influencing patients' choice for having contralateral prophylactic mastectomy (CPM)., Methods: This is a retrospective study of 373 patients diagnosed with primary invasive breast cancer who were treated by bilateral or unilateral mastectomy (BM or UM) at the Revlon/UCLA Breast Center between Jan. 2002 and Dec. 2010. In the BM group, only those with unilateral breast cancer who chose CPM were included in the analysis., Results: When compared with the UM group, the following factors were found to be associated with BM: younger age, pre-menopausal, a family history of breast/ovarian cancer, BRCA mutation, more breast biopsies, history of breast augmentation, having MRI study within 6 months before the surgery, more likely to have reconstruction and sentinel lymph node biopsy (SLNB) and fewer had neoadjuvant/adjuvant chemotherapy/radiation. When patients with bilateral breast cancer were excluded, multivariate logistic regression analysis indicated younger patients with negative nodes, SLNB as the only nodal surgery and positive family history were significant factors predicting CPM and immediate reconstruction using tissue expanders or implants., Conclusion: Younger age, lower TN stage, requiring only SLNB and high risk family history predict contralateral prophylactic mastectomy. Tissue expander/implant-based reconstructions were more frequently chosen by patients with BM.

Identification of protein targets that play a role in breast cancer invasion may help to understand the rapid progression of cancer and may lead to the development of new biomarkers for the disease. In this study, we compared two highly invasive and two poorly invasive breast cancer cell lines using comparative label-free LC-MS profiling in order to identify differentially expressed proteins that may be linked to the invasive phenotype in vitro. Forty-five proteins were found to be upregulated, and 34 proteins, downregulated. UV excision repair protein RAD23 homologue B (RAD23B) was found among the downregulated proteins in highly invasive breast cancer cell lines. In poorly invasive breast cancer cell lines, siRNA-mediated downregulation of RAD23B subsequently led to an increase in invasion and adhesion in vitro. Immunohistochemistry analysis of 164 specimens of invasive breast cancer showed that having a high percentage (>80%) of RAD23B positive nuclei was significantly associated with histopathological grades 1 and 2 breast cancer and with low mitotic activity. In addition, a high staining intensity for RAD23B in the cytoplasm was significantly associated with histopathological grade 3 breast cancer. This study suggests a potential role of RAD23B in breast cancer progression and may further imply a tumor suppressor role of nuclear RAD23B in breast cancer.

Accumulating data have shown the involvement of microRNAs in cancerous processes as either oncogenes or tumor suppressor genes. Here, we established miR-30a as a tumor suppressor gene in breast cancer development and metastasis. Ectopic expression of miR-30a in breast cancer cell lines resulted in the suppression of cell growth and metastasis in vitro. Consistently, the xenograft mouse model also unveiled the suppressive effects of miR-30a on tumor growth and distal pulmonary metastasis. With dual luciferase reporter assay, we revealed that miR-30a could bind to the 3'-untranslated region of metadherin (MTDH) gene, thus exerting inhibitory effect on MTDH. Furthermore, we demonstrated that silence of MTDH could recapitulate the effects of miR-30a overexpression, while overexpression of MTDH could partially abrogate miR-30a-mediated suppression. Of significance, expression level of miR-30a was found to be significantly lower in primary breast cancer tissues than in the paired normal tissues. Further evaluation verified that miR-30a was negatively correlated with the extent of lymph node and lung metastasis in patients with breast cancer. Taken together, our findings indicated miR-30a inhibits breast cancer proliferation and metastasis by directly targeting MTDH, and miR-30a can serve as a prognostic marker for breast cancer. Manipulation of miR-30a may provide a promising therapeutic strategy for breast cancer treatment.

Purpose: We investigated rates of occult malignancy in the breast and sentinel lymph nodes (SLNs) in patients undergoing prophylactic mastectomy (PM) and whether routine sentinel lymph node biopsy (SLNB) is justified., Methods: A retrospective review of our database identified patients undergoing PMs with SLNB. Descriptive statistics were utilized for data summary. A P value of <0.05 was considered significant., Results: There were 384 patients during the study period who underwent 467 PMs. Of the 467 PMs, 15 (3.2%) cancers were found on final pathology. All 6 of the invasive cancers identified were T1. A total of 682 SLNs were taken for an average of 1.46 SLNs per PM. There were 5 positive SLNs (1.1%). All were in patients undergoing contralateral PM for either history of breast cancer or new diagnosis of breast cancer. Only one patient with a positive SLN was found to have an occult breast malignancy in the PM specimen., Conclusion: In 467 PMs performed, 15 (3.2%) occult malignancies were found in the breast and 5 (1.1%) positive SLNs were found. Based on these results, the routine use of SLNB at the time of PM is unnecessary and does not warrant the morbidity associated with this procedure., (© 2014 Wiley Periodicals, Inc.)

Epithelial-mesenchymal transition (EMT) and cellular invasiveness are two pivotal processes for the development of metastatic tumor phenotypes. The metastatic profile of non-metastatic MCF-7 cells growing as multi-cellular tumor microspheroids (MCTSs) was analyzed by determining the contents of the EMT, invasive and migratory proteins, as well as their migration and invasiveness potential and capacity to secrete active cytokines such as the glucose phosphate isomerase/AMF (GPI/AMF). As for the control, the same analysis was also performed in MCF-7 and MDA-MB-231 (highly metastatic, MDA) monolayer cells, and in stage IIIB and IV human metastatic breast biopsies. The proliferative cell layers (PRL) of mature MCF-7 MCTSs, MDA monolayer cells and metastatic biopsies exhibited increased cellular contents (2-15 times) of EMT (β-catenin, SNAIL), migratory (vimentin, cytokeratin, and fibronectin) and invasive (MMP-1, VEGF) proteins versus MCF-7 monolayer cells, quiescent cell layers of mature MCF-7 MCTS and non-metastatic breast biopsies. The increase in metastatic proteins correlated with substantially elevated cellular abilities for migration (18-times) and invasiveness (13-times) and with the higher level (6-times) of the cytokine GPI/AMF in the extracellular medium of PRL, as compared to MCF-7 monolayer cells. Interestingly, the addition of the GPI/AMF inhibitors erythrose-4-phosphate or 6-phosphogluconate at micromolar doses significantly decreased its extracellular activity (>80%), with a concomitant diminution in the metastatic protein content and migratory tumor cell capacity, and with no inhibitory effect on tumor lactate production or toxicity on 3T3 mouse fibroblasts. The present findings provide new insights into the discovery of metabolic inhibitors to be used as complementary therapy against metastatic and aggressive tumors., (Copyright © 2014. Published by Elsevier B.V.)

Ductal carcinoma in situ (DCIS) is a nonmalignant lesion of the breast with the potential to progress to invasive ductal carcinoma (IDC). The disappearance and breakdown of the myoepithelial cell layer and basement membrane in DCIS have been identified as major events in the development of breast cancer. The MCF10DCIS.com cell line is a well-established model, which recapitulates the progression of breast cancer from DCIS to IDC. We have previously reported that a novel Gemini vitamin D analog, 1α,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-cholecalciferol (BXL0124) is a potent inhibitor of the growth of MCF10DCIS.com xenografted tumors without hypercalcemic toxicity. In this study, we utilized the MCF10DCIS.com in vivo model to assess the effects of BXL0124 on breast cancer progression from weeks 1 to 4. Upon DCIS progression to IDC from weeks 3 to 4, tumors lost the myoepithelial cell layer and basement membrane as shown by immunofluorescence staining with smooth muscle actin and laminin 5, respectively. Administration of BXL0124 maintained the critical myoepithelial cell layer as well as basement membrane, and animals treated with BXL0124 showed a 43% reduction in tumor volume by week 4. BXL0124 treatment decreased cell proliferation and maintained vitamin D receptor levels in tumors. In addition, the BXL0124 treatment reduced the mRNA levels of matrix metalloproteinases starting at week 3, contributing to the inhibition of invasive transition. Our results suggest that the maintenance of DCIS plays a significant role in the cancer preventive action of the Gemini vitamin D BXL0124 during the progression of breast lesions., (©2014 American Association for Cancer Research.)

Prophylactic skin-sparing mastectomy (SSM) is associated with major breast cancer risk reduction in high-risk patients. In prophylactic nipple-sparing mastectomy (NSM) it is unknown how many terminal duct lobular units (TDLUs) remain behind the nipple-areola complex (NAC) additionally to those behind the skin flap. Therefore, safety of NSM can be doubted. We compared amounts of TDLUs behind the NAC as compared with the skin. In prophylactic SSM and conventional therapeutic mastectomy patients, the NAC and an adjacent skin island (SI) were resected as if it were an NSM. NAC and SI were serially sectioned perpendicularly to the skin and analyzed for the amount of TDLUs present. Slides of NAC and SI were scanned, and slide surface areas (cm) were measured. TDLUs/cm in NAC versus SI specimen, representing TDLU density, were analyzed pairwise. In total, 105 NACs and SIs of 90 women were analyzed. Sixty-four NACs (61%) versus 25 SIs (24%) contained ≥1 TDLUs. Median TDLU density was higher in NAC specimens (0.2 TDLUs/cm) as compared with SI specimens (0.0 TDLUs/cm; P<0.01). Independent risk factors for the presence of TDLUs in the NAC specimen were younger age and parity (vs. nulliparity). The finding of higher TDLU density behind the NAC as compared with the skin flap suggests that sparing the NAC in prophylactic NSM in high-risk patients possibly may increase postoperative breast cancer risk as compared with prophylactic SSM. Studies with long-term follow-up after NSM are warranted to estimate the level of residual risk.

Background: Aromatase inhibitors effectively prevent breast cancer recurrence and development of new contralateral tumours in postmenopausal women. We assessed the efficacy and safety of the aromatase inhibitor anastrozole for prevention of breast cancer in postmenopausal women who are at high risk of the disease., Methods: Between Feb 2, 2003, and Jan 31, 2012, we recruited postmenopausal women aged 40-70 years from 18 countries into an international, double-blind, randomised placebo-controlled trial. To be eligible, women had to be at increased risk of breast cancer (judged on the basis of specific criteria). Eligible women were randomly assigned (1:1) by central computer allocation to receive 1 mg oral anastrozole or matching placebo every day for 5 years. Randomisation was stratified by country and was done with blocks (size six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation; only the trial statistician was unmasked. The primary endpoint was histologically confirmed breast cancer (invasive cancers or non-invasive ductal carcinoma in situ). Analyses were done by intention to treat. This trial is registered, number ISRCTN31488319., Findings: 1920 women were randomly assigned to receive anastrozole and 1944 to placebo. After a median follow-up of 5·0 years (IQR 3·0-7·1), 40 women in the anastrozole group (2%) and 85 in the placebo group (4%) had developed breast cancer (hazard ratio 0·47, 95% CI 0·32-0·68, p<0·0001). The predicted cumulative incidence of all breast cancers after 7 years was 5·6% in the placebo group and 2·8% in the anastrozole group. 18 deaths were reported in the anastrozole group and 17 in the placebo group, and no specific causes were more common in one group than the other (p=0·836)., Interpretation: Anastrozole effectively reduces incidence of breast cancer in high-risk postmenopausal women. This finding, along with the fact that most of the side-effects associated with oestrogen deprivation were not attributable to treatment, provides support for the use of anastrozole in postmenopausal women at high risk of breast cancer., Funding: Cancer Research UK, the National Health and Medical Research Council Australia, Sanofi-Aventis, and AstraZeneca., (Copyright © 2014 Cuzick et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.)

Background: Contralateral prophylactic mastectomy (CPM) removes the non-diseased breast in women who have unilateral breast cancer. This reduces the incidence of contralateral breast cancer, and potentially improves survival in high risk patients. Such surgical risk-reduction strategy is increasingly being adopted in the United States, despite a decreasing incidence of contralateral breast cancer. The use of CPM in an Asian population is yet unknown. We present the first Asian report on CPM rates and trends in Singapore, the country with the highest incidence of breast cancer in Asia., Methods: A retrospective review of all patients who had breast cancer surgery from 2001 to 2010 at the largest healthcare system in Singapore was performed. Patient demographics and tumour characteristics were analysed with regards to type of surgery performed. Factors associated with CPM were identified., Results: From 2001 to 2010, a total of 5130 patients underwent oncological breast surgery. A decreasing trend of mastectomies (82.7%-70.8%), an upward trend of breast conserving surgery (BCS) (17.3%-29.2%) and an increasing trend in CPM (0.46%-1.25%) is observed. Patients who opted for CPM are likely to be younger (48.4 ± 9.4 years), married (60%), parous (56.7%), with no family history of breast/ovarian cancer (66.7%), and diagnosed at an earlier stage. The rate of synchronous occult breast malignancy was found to be 10% (n = 30), and these were in patients who were of a low cancer-risk profile., Conclusions: This retrospective study reflects an increasing incidence of breast cancer in Singapore, with a decrease in mastectomies, and an increase in BCS and CPM rates, similar to Western data. Similar to Western populations, the Asian woman who opts for CPM is likely to be young and have an earlier stage of breast cancer. In contrast, the Asian woman is likely to have no family history of breast or ovarian cancers. Commonly cited reasons for increased CPM rates such as the increased availability of genetic counselling and pre-operative MRI evaluation, along with wide use of reconstruction, do not feature as dominant factors in our population, suggesting that the Asian patients may have different considerations when electing for CPM., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Corresponding to the increased use of mammography, the incidence of ductal carcinoma in situ (DCIS) has risen dramatically in the past 30 years. Despite its growing incidence, the treatment of DCIS remains highly variable and controversial. Although DCIS itself does not metastasize and is never lethal, it may be a precursor of invasive breast cancer and is a marker of increased breast cancer risk. Confusing a precursor lesion with cancer, many clinicians apply an invasive breast cancer treatment paradigm to DCIS patients, offering adjuvant radiation therapy and tamoxifen after diagnosis. In this commentary, we outline the issues associated with DCIS management--is DCIS a cancer, a precursor of cancer, or a marker of invasive carcinoma risk? Specifically, we argue that consideration be given to removing the term "carcinoma" from DCIS, using cancer "occurrence" to mean the diagnosis of invasive cancer after DCIS instead of "recurrence," and make the argument that a prophylactic paradigm of treatment after excision may be more appropriate.

Nipple-sparing mastectomy (NSM) as a therapeutic or prophylactic procedure for breast cancer is rapidly gaining popularity as the literature continues to support it safety. The lateral inframammary fold (IMF) approach provides adequate exposure and eliminates visible scars on the anterior surface of the breast, making this incision cosmetically superior to radial or periareolar approaches. We reviewed 55 consecutive NSMs performed through a lateral IMF incision with immediate implant-based reconstruction, with or without tissue expansion, between June 2008 and June 2011. Prior to incision, breasts were lightly infiltrated with dilute anesthetic solution with epinephrine. Sharp dissection, rather than electrocautery, was used as much as possible to minimize thermal injury to the mastectomy flap. When indicated, acellular dermal matrix was placed as an inferolateral sling. Subsequent fat grafting to correct contour deformities was performed in select patients. Three-dimensional (3D) photographs assessed changes in volume, antero-posterior projection, and ptosis. Mean patient age was 46 years, and mean follow-up time was 12 months. Twelve mastectomies (22%) were therapeutic, and the remaining 43 (78%) were prophylactic. Seven of the nine sentinel lymph node biopsies (including one axillary dissection) (78%) were performed through the lateral IMF incision without the need for a counter-incision. Acellular dermal matrix was used in 34 (62%) breasts. Average permanent implant volume was 416 cc (range 176-750 cc), and average fat grafting volume was 86 cc (range 10-177 cc). In one patient a positive intraoperative subareolar biopsy necessitated resection of the nipple-areola complex (NAC), and in two other patients NAC resection was performed at a subsequent procedure based on the final pathology report. Mastectomy flap necrosis, requiring operative debridement, occurred in two breasts (4%), both in the same patient. One of these breasts required a salvage latissimus dorsi myocutaneous flap to complete the reconstruction. Three nipples (6%) required office debridement for partial necrosis and operative reconstruction later. No patient had complete nipple necrosis. No statistically significant differences existed between therapeutic and prophylactic mastectomies for developing partial skin and/or nipple necrosis (p = 0.35). Three episodes (5%) of cellulitis occurred, which responded to antibiotics without the need for explantation. Morphological outcomes using 3D scan measurements showed reconstructed breasts were larger, more projected, and less ptotic than the preoperative breasts (196 versus 248 cc, 80 versus 90 mm, 146 versus 134 mm, p < 0.01 for each parameter). Excellent results can be achieved with immediate implant-based reconstruction of NSM through a lateral IMF incision. NAC survival is reliable, and complication rates are low., (© 2012 Wiley Periodicals, Inc.)

Introduction: In keeping with recently documented national trends, a significant and increasing number of patients will have chosen contralateral prophylactic mastectomy (CPM) based on personal preference, without traditional clinical or pathological indication., Methods: Women who underwent CPM at the University of Louisville from 2003 to 2009 were selected for this study. Descriptive factors were evaluated such as age, race, family history of breast cancer, laterality, hormone receptor status, stage, grade and histology of the index breast lesion. Statistical analysis was used to compute predictive factors for occult contralateral pathology., Results: A total of 107 patients underwent CPM and had adequate medical information to be included in this study. The median age was 48 years, with 88% being white and 12% being African American. Seventy-six percent of the index breast cancers were infiltrating ductal carcinoma and 12% were infiltrating lobular carcinoma. Five "significant" occult pathologies were found in the prophylactically removed breast. Two of the lesions were ductal carcinoma in situ, 2 were lobular carcinoma in situ and 1 was an invasive mucinous carcinoma. On bivariate analysis, there were no factors identified predictive for occult contralateral pathology., Conclusions: In line with previously reported data, we noted that fewer than 5% of patients who underwent CPM had pathology in the contralateral breast. We were unable to correlate any clinical or pathological characteristics in women who presented with contralateral breast cancer. This study raises serious questions regarding the clinical utility of CPM in detecting synchronous clinically and radiographically occult contralateral primaries.

Women with atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS), and severe ADH are at increased risk of breast cancer, but a systematic quantification of this risk and the efficacy of chemoprevention in the clinical setting is still lacking. The objective of this study is to evaluate a woman's risk of breast cancer based on atypia type and to determine the effect of chemoprevention in decreasing this risk. Review of 76,333 breast pathology reports from three institutions within Partners Healthcare System, Boston, from 1987 to 2010 using natural language processing was carried out. This approach identified 2,938 women diagnosed with atypical breast lesions. The main outcome of this study is breast cancer occurrence. Of the 2,938 patients with atypical breast lesions, 1,658 were documented to have received no chemoprevention, and 184/1,658 (11.1 %) developed breast cancer at a mean follow-up of 68 months. Estimated 10-year cancer risks were 17.3 % with ADH, 20.7 % with ALH, 23.7 % with LCIS, and 26.0 % with severe ADH. In a subset of patients treated from 1999 on (the chemoprevention era), those who received no chemoprevention had an estimated 10-year breast cancer risk of 21.3 %, whereas those treated with chemoprevention had a 10-year risk of 7.5 % (p < 0.001). Chemoprevention use significantly reduced breast cancer risk for all atypia types (p < 0.05). The risk of breast cancer with atypical breast lesions is substantial. Physicians should counsel patients with ADH, ALH, LCIS, and severe ADH about the benefit of chemoprevention in decreasing their breast cancer risk.

Background: Although physical activity reduces breast cancer risk, issues critical to providing clear public health messages remain to be elucidated. These include the minimum duration and intensity necessary for risk reduction and the optimal time period for occurrence, as well as subgroup effects, particularly with regard to tumor heterogeneity and body size., Methods: This study investigated the relationship between recreational physical activity (RPA) and breast cancer risk, in addition to characterizing the joint effects of activity level, weight gain, and body size, through use of a population-based sample of 1504 cases (N = 233 in situ, N = 1271 invasive) and 1555 controls (aged 20-98 years) from the Long Island Breast Cancer Study Project, in Long Island, New York., Results: A nonlinear dose-response association was observed between breast cancer risk and RPA during the reproductive period and after menopause. Women in the third quartile of activity experienced the greatest benefit with an approximate 30% risk reduction for reproductive (odds ratio = 0.67; 95% confidence interval = 0.48-0.94) and postmenopausal activity (odds ratio = 0.70; 95% confidence interval = 0.52-0.95). Little to no difference was observed regarding intensity of activity or hormone receptor status. Joint assessment of RPA, weight gain, and body size revealed that women with unfavorable energy balance profiles were at increased breast cancer risk. A significant multiplicative interaction was observed between RPA and adult weight gain (P = .033)., Conclusions: RPA at any intensity level during the reproductive and postmenopausal years have the greatest benefit for reducing breast cancer risk. Substantial postmenopausal weight gain may eliminate the benefits of regular activity., (Copyright © 2012 American Cancer Society.)

The Generations trial, a multicenter, placebo-controlled, double-blind trial, compared arzoxifene 20 mg/day and placebo in 9,354 postmenopausal women with osteoporosis (N=5,252) or low bone mass (N=4,102). Primary outcomes were vertebral fracture in the osteoporotic population and invasive breast cancer in all study participants. Here, we report the detailed breast cancer findings from the trial. Breast cancers were detected by annual mammograms and clinical examination. After 48 months follow-up, breast cancer incidence was compared between treatment groups by estrogen receptor (ER) and progesterone receptor (PR) status and baseline risk factors. Baseline breast cancer risk factors, including age, estimated Gail risk, and bone mineral density, were well balanced between treatment groups. A total of 75 breast cancers occurred 53 in the placebo group and 22 in the arzoxifene group (HR 0.41, 95% CI 0.25-0.68, P<0.001). There were 62 invasive breast cancers, 39 identified as invasive ER-positive (placebo 30, arzoxifene 9; HR 0.30, 95% CI 0.14-0.63, P=0.001) and 30 identified as invasive PR-positive (placebo 23, arzoxifene 7; HR 0.30, 95% CI 0.13-0.71, P=0.003). Breast cancer risk reduction with arzoxifene was similar between Gail risk groups (P interaction=0.31) and between low bone mass and osteoporosis groups (P interaction=0.35). Although generally well tolerated, there was a significant increase in venous thromboembolism, vasomotor symptoms, muscle cramps, and some gynecological events with arzoxifene. These findings demonstrate that in this study arzoxifene reduced the risk of ER-positive breast cancer in this population of postmenopausal women with low bone mass or osteoporosis, an effect similar to that seen with other SERMs.

Introduction: Most women who have screening mammography and undergo subsequent open biopsy following an indeterminate core biopsy result are eventually found to have benign disease. However, a significant number have malignant disease and the rate of malignancy in such cases may be influenced by various factors. This study examined the effect of the type of screening round (prevalent or incident) on the likelihood of breast cancer being present., Methods: A total of 199 women who had NHS breast screening mammograms and subsequent indeterminate (B3) core biopsy results followed by excision biopsy over an 11-year period in a single breast screening unit were reviewed., Results: The rate of malignancy following excision of a lesion graded as B3 on core biopsy was 21% for women in the prevalent screening round compared to 33% in subsequent rounds (Fisher's exact test, p=0.038)., Conclusions: The incidence of malignancy associated with a B3 core biopsy result appears to be related to the screening round in which the lesion is detected, being approximately 50% higher in the subsequent incident rounds compared to the initial prevalent round. This finding may be useful in formulating management plans for women who have an indeterminate biopsy result.

Background: Breast cancer is the second mortality-related cancer and the leading cause of general mortality in women aged 40-55. Prophylactic mastectomy has proved to be effective in several clinical scenarios but is still a somewhat controversial procedure., Methods: We performed a retrospective study by reviewing the records of all patients who underwent prophylactic mastectomy in a 25-year period. We evaluated the aesthetic and long-term oncologic outcomes, complications, and patient satisfaction., Results: We had 52 patients, 40 of them unilateral cases (contralateral prophylactic mastectomy) and 12 bilateral (bilateral prophylactic mastectomy) for a total of 64 mastectomized breasts. We had 1 (1.56%) case of unexpected breast cancer in the mastectomy specimens. Forty-two (65.62%) cases had a subcutaneous prophylactic mastectomy and 22 (34.37%) cases had a simple total prophylactic mastectomy. Fifty-eight (90.62%) cases underwent reconstruction with alloplastics and 6 (9.37) cases with autologous tissue of which 5 (7.81%) cases received latissimus dorsi flaps with alloplastic implants and 1 (1.56%) case had a TRAM flap. The complications included 4 (6.25%) breasts that developed capsular contracture, 2 (3.12%) cases of hematoma, and 1 (1.56%) infection. Concerning patient satisfaction, 39 (75%) patients reported being highly satisfied, 10 (19.23%) partially satisfied, and 3 (5.76%) unsatisfied. When we performed the aesthetic evaluation according to our scale, we got an overall aesthetic index of 8.8., Conclusion: Prophylactic mastectomy is becoming an increasingly frequent procedure. Plastic surgeons should consider the aesthetic outcome when planning mastectomy and reconstruction. Our ability to predict the high-risk population has improved and it is that population who can get the best benefit from this intervention. The recommendation against subcutaneous prophylactic mastectomy lacks scientific evidence. There is plenty of evidence that prophylactic mastectomy lowers the risk of breast cancer in the high-risk population in at least 95%. Our experience with prophylactic mastectomy is extremely satisfactory, with an overall patient satisfaction rate of 94%, no mortality, and an oncologic long-term outcome of 0% of ulterior development of breast cancer. Our series, although relatively small, should provide some insight into the power of this technique and we think all plastic surgeons should have it in their surgical armamentarium and should share their experiences so that this procedure may become more widely accepted. We also think that plastic surgeons should strive for perfecting the technique to reduce the complication rate and therefore help the procedure gain acceptance by the medical community.

Purpose of Review: For women aged 40-49 years, to describe the benefits and harms of performing screening mammography, accuracy of digital mammography, and new evidence on the effectiveness of risk-based screening., Recent Findings: New data support a 15% reduction in breast cancer mortality for women aged 40-49 years after 10 years of screening; however, the absolute benefit is small and not outweighed by important harms. Digital mammography is more sensitive, but less specific than film mammography in women aged 40-49 years. Risk-based screening that identifies and screens women aged 40-49 years with breast cancer risk similar to an average-risk woman aged 50-59 years results in similar benefits and harms of screening these high-risk women as screening average-risk 50-year-old women., Summary: Practitioners should discuss with women aged 40-49 years the benefits and harms of undergoing screening mammography before offering them screening. If women elect to undergo screening mammography, they should undergo biennial screening with digital mammography. Targeting screening for those women aged 40-49 years with risk factors that substantially increase the risk of breast cancer, such as high breast density, family history of breast cancer, and history of benign breast biopsy, could maximize the benefits and minimizes the harms of screening this age group.

Introduction: Endocrine therapy with selective estrogen receptor modulators (SERMs) has been the mainstay of breast cancer prevention trials to date. The aromatase inhibitors, which inhibit the final chemical conversion of androgens to estrogens, have shown increased disease-free survival benefit over tamoxifen in patients with primary hormone receptor-positive breast cancer, as well as reducing the risk of developing contralateral breast cancers. The aromatase inhibitors are being actively evaluated as prevention agents for women with a history of ductal carcinoma in situ as well as for women who are considered to be at high risk for developing primary invasive breast cancer., Areas Covered: This review evaluates the available prevention data, as evidenced by the decrease in contralateral breast cancers, when aromatase inhibitors are used in the adjuvant setting, as well as the emerging data of the aromatase inhibitors specifically tested in the prevention setting for women at high risk., Expert Opinion: Exemestane is a viable option for breast cancer prevention. We continue to await further follow-up on exemestane as well as other aromatase inhibitors in the prevention setting for women at high risk of developing breast cancer or with a history of ductal carcinoma in situ.

To estimate the impact of early detection of cancer, knowledge of how quickly primary tumors grow and at what size they shed lethal metastases is critical. We developed a natural history model of cancer to estimate the probability of disease-specific cure as a function of tumor size, the tumor volume doubling time (TVDT), and disease-specific mortality reduction achievable by screening. The model was applied to non-small-cell lung carcinoma (NSCLC) and invasive ductal carcinoma (IDC), separately. Model parameter estimates were based on Surveillance Epidemiology and End Results (SEER) cancer registry datasets and validated on screening trials. Compared to IDC, NSCLC is estimated to have a lower probability of disease-specific cure at the same detected tumor size, shed lethal metastases at smaller sizes (median: 19 mm for IDC versus 8 mm for NSCLC), have a TVDT that is almost half as long (median: 252 days for IDC versus 134 days for NSCLC). Consequently, NSCLC is associated with a lower mortality reduction from screening at the same screen detection threshold and screening interval. In summary, using a similar natural history model of cancer, we quantify the disease-specific curability attributable to screening for breast cancer, and separately lung cancer, in terms of the TVDT and onset of lethal metastases.