Breast Cancer following Augmentation Mammaplasty: A Case-Control Study.

BACKGROUND: The purpose of this study was to determine whether augmentation mammaplasty, implant type, and implant location affect breast cancer detection, stage, and treatment. METHODS: An institutional case-control study was performed of patients with prior breast augmentation undergoing breast cancer treatment from 2000 to 2013. Controls were propensity matched and randomized, and data were retrospectively reviewed. RESULTS: Forty-eight cases and 302 controls were analyzed. Palpable lesions were detected at a smaller size in augmentation patients (1.6 cm versus 2.3 cm; p < 0.001). Fewer lesions in augmented patients were detected by screening mammography (77.8 percent of cases versus 90.7 percent of controls; p = 0.010). Patients with implants were more likely to undergo an excisional biopsy for diagnosis (20.5 percent versus 4.4 percent; p < 0.001), rather than image-guided core needle biopsy (77.3 percent versus 95.3 percent; p < 0.001). Earlier staging in augmented patients approached but did not reach statistical significance (p = 0.073). Augmented patients had higher mastectomy rates (74.5 percent versus 57.0 percent) and lower rates of breast-conservation therapy (25.5 percent versus 43 percent; p = 0.023). Neither implant fill type nor anatomic location affected method of diagnosis, stage, or treatment. CONCLUSIONS: Palpable detection of breast cancer is more likely at a smaller size in augmented patients, yet it is less likely on screening mammography than in controls. Augmentation breast cancer patients have a comparable disease stage and are more likely to undergo mastectomy rather than lumpectomy. Both silicone and saline implants, whether placed submuscularly or subglandularly, have comparable effects on breast imaging, biopsy modality, and surgical intervention. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Comparison of Different Acellular Dermal Matrices in Breast Reconstruction: The 50/50 Study.

BACKGROUND: Acellular dermal matrix has enjoyed extensive use in primary and secondary alloplastic breast aesthetic and reconstructive surgery. The objective of this study was to examine clinical outcomes between available acellular dermal matrix products: DermACELL (LifeNet Health, Virginia Beach, Va.) and AlloDerm Ready To Use (LifeCell Corp., Branchburg, N.J.). METHODS: A retrospective chart review was performed on 58 consecutive patients (100 breasts) reconstructed with either DermACELL (n = 30 patients; 50 breasts) or AlloDerm Ready To Use (n = 28 patients; 50 breasts). The mastectomies were performed by three different breast surgeons. All reconstructions were performed by the same plastic surgeon (T.A.P.). Statistical analysis was performed by means of Fisher's exact test. RESULTS: Differences in the average age, body mass index, percentage having neoadjuvant/adjuvant chemotherapy or breast irradiation, and numbers of therapeutic and prophylactic mastectomies between the two groups were not statistically significant (p < 0.05). Complications in both cohorts of patients were clinically recorded for 90 days after immediate reconstruction. When comparing outcomes, patients in the DermACELL group had a significantly lower incidence of "red breast syndrome" (0 percent versus 26 percent; p = 0.0001) and fewer days before drain removal (15.8 days versus 20.6 days; p = 0.017). No significant differences were seen in terms of seroma, hematoma, delayed healing, infection, flap necrosis, or explantation. CONCLUSION: Patients reconstructed with DermACELL as compared with AlloDerm Ready To Use have significantly decreased number of days to drain removal and red breast syndrome and equivalent rates of other complications, including seroma, infection, flap necrosis, and explantation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Landscape of genome-wide age-related DNA methylation in breast tissue.

Despite known age-related DNA methylation (aDNAm) changes in breast tumors, little is known about aDNAm in normal breast tissues. Breast tissues from a cross-sectional study of 121 cancer-free women, were assayed for genome-wide DNA methylation. mRNA expression was assayed by microarray technology. Analysis of covariance was used to identify aDNAm's. Altered methylation was correlated with expression of the corresponding gene and with DNA methyltransferase protein DNMT3A, assayed by immunohistochemistry. Publically-available TCGA-BRCA data were used for replication. 1,214 aDNAm's were identified; 97% with increased methylation, and all on autosomes. Sites with increased methylation were predominantly in CpG lslands and non-enhancers. aDNAm's with decreased methylation were generally located in intergenic regions, non-CpG Islands, and enhancers. Of the aDNAm's identified, 650 are known to be involved in cancer, including ESR1 and beta-estradiol responsive genes. Expression of DNMT3A was positively associated with age. Two aDNAm's showed borderline significant associations with DNMT3A expression; KRR1 (OR 6.57, 95% CI: 2.51-17.23) and DHRS12 (OR 6.08, 95% CI: 2.33-15.86). A subset of aDNAm's co-localized within vulnerable regions for somatic mutations in cancers including breast cancer. Expression of C19orf48 was inversely and significantly correlated with its methylation level. In the TCGA dataset, 84% and 64% of the previously identified aDNAm's were correlated with age in both normal-adjacent and tumor breast tissues, with differential associations by histological subtype. Given the similarity of findings in the breast tissues of healthy women and breast tumors, aDNAm's may be one pathway for increased breast cancer risk with age.

Discovery and replication of microRNAs for breast cancer risk using genome-wide profiling.

BACKGROUND: Genome-wide miRNA expression may be useful for predicting breast cancer risk and/or for the early detection of breast cancer. RESULTS: A 41-miRNA model distinguished breast cancer risk in the discovery study (accuracy of 83.3%), which was replicated in the independent study (accuracy = 63.4%, P=0.09). Among the 41 miRNA, 20 miRNAs were detectable in serum, and predicted breast cancer occurrence within 18 months of blood draw (accuracy 53%, P=0.06). These risk-related miRNAs were enriched for HER-2 and estrogen-dependent breast cancer signaling. MATERIALS AND METHODS: MiRNAs were assessed in two cross-sectional studies of women without breast cancer and a nested case-control study of breast cancer. Using breast tissues, a multivariate analysis was used to model women with high and low breast cancer risk (based upon Gail risk model) in a discovery study of women without breast cancer (n=90), and applied to an independent replication study (n=71). The model was then assessed using serum samples from the nested case-control study (n=410). CONCLUSIONS: Studying breast tissues of women without breast cancer revealed miRNAs correlated with breast cancer risk, which were then found to be altered in the serum of women who later developed breast cancer. These results serve as proof-of-principle that miRNAs in women without breast cancer may be useful for predicting breast cancer risk and/or as an adjunct for breast cancer early detection. The miRNAs identified herein may be involved in breast carcinogenic pathways because they were first identified in the breast tissues of healthy women.

The Safety, Effectiveness, and Efficiency of Autologous Fat Grafting in Breast Surgery.

BACKGROUND: For years, the safety and effectiveness of autologous fat grafting (AFG) for breast reconstruction have been in question, with particular concern over fat necrosis, calcifications, cyst formation, and interfering with the detection of breast cancer. However, increasing evidence suggests that the complication rates and clinical results are generally acceptable to both clinicians and patients. The emerging challenge is the numerous AFG techniques and systems, where there are limited knowledge and data. The objective of this study was to conduct a literature review that focuses on the safety, effectiveness, and efficiency of various AFG techniques as applied to the breast. METHODS: A PubMed search using terms related to AFG was performed over a 5-year period (April 1, 2010-April 30, 2015). Original articles focused on AFG to the breast, with outcomes on safety, effectiveness, and efficiency, were included. RESULTS: Five hundred ninety-eight articles were identified with 36 articles included (n = 4306 patients). Satisfaction rates were high although the prevalence of complications was low-similar to previous findings. Seven studies reported average operating room time with an overall mean of 125 minutes (range: 40-210). The mean volume of fat harvested was 558 mL (range: 120-1299), and fat injected was 145 mL (range: 20-607). A positive association between injection volume and operating time was observed. CONCLUSIONS: This review validates previous findings on the safety and effectiveness of AFG to the breast and highlights its efficiency. The efficiency data available, although limited, suggest that there is an opportunity to achieve time and cost savings while not sacrificing safety and effectiveness.

Management of the High-Riding Nipple After Breast Reduction.

Postoperative nipple malposition can be an aesthetically devastating problem for patients and a formidable challenge for surgeons. Reduction mammoplasty often includes plans to elevate the nipple-areolar complex (NAC); however, overelevation should be avoided. Its management is complicated because of the limited amount of skin between the nipple and the sternal notch and the desire to avoid creating scars that lie above the nipple in the superior aspect of the breast. Although superior malposition of the NAC should and can be prevented, there are direct and indirect surgical techniques that can assist in repositioning the NAC to an acceptable location.

Genetic variation in one-carbon metabolism in relation to genome-wide DNA methylation in breast tissue from heathy women.

Single nucleotide polymorphisms (SNPs) in one-carbon metabolism genes and lifestyle factors (alcohol drinking and breast folate) may be determinants of whole-genome methylation in the breast. DNA methylation profiling was performed using the Illumina Infinium HumanMethylation450 BeadChip in 81 normal breast tissues from women undergoing reduction mammoplasty and no history of cancer. ANCOVA, adjusting for age, race and BMI, was used to identify differentially-methylated (DM) CpGs. Gene expression, by the Affymetrix GeneChip Human Transcriptome Array 2.0, was correlated with DM. Biological networks of DM genes were assigned using Ingenuity Pathway Analysis. Fifty-seven CpG sites were DM in association with eight SNPs in FTHFD, MTHFD1, MTHFR, MTR, MTRR, and TYMS (P <5.0 x 10-5); 56% of the DM CpGs were associated with FTHFD SNPs, including DM within FTHFD. Gene expression was negatively correlated with FTHFD methylation (r=-0.25, P=0.017). Four DM CpGs identified by SNPs in MTRR, MTHFR, and FTHFD were significantly associated with alcohol consumption and/or breast folate. The top biological network of DM CpGs was associated with Energy Production, Molecular Transportation, and Nucleic Acid Metabolism. This is the first comprehensive study of the association between SNPs in one-carbon metabolism genes and genome-wide DNA methylation in normal breast tissues. These SNPs, especially FTHFD, as well as alcohol intake and folate exposure, appear to affect DM in breast tissues of healthy women. The finding that SNPs in FTHFD and MTR are associated with their own methylation is novel and highlights a role for these SNPs as cis-methylation quantitative trait loci.

Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues.

Genome-wide DNA hypomethylation is an early event in the carcinogenic process. Percent methylation of long interspersed nucleotide element-1 (LINE-1) is a biomarker of genome-wide methylation and is a potential biomarker for breast cancer. Understanding factors associated with percent LINE-1 DNA methylation in histologically normal tissues could provide insight into early stages of carcinogenesis. In a cross-sectional study of 121 healthy women with no prior history of cancer who underwent reduction mammoplasty, we examined associations between plasma and breast folate, genetic variation in one-carbon metabolism, and percent LINE-1 methylation using multivariable regression models (adjusting for race, oral contraceptive use, and alcohol use). Results are expressed as the ratio of LINE-1 methylation relative to that of the referent group, with the corresponding 95% confidence intervals (CI). We found no significant associations between plasma or breast folate and percent LINE-1 methylation. Variation in MTHFR, MTR, and MTRR were significantly associated with percent LINE-1 methylation. Variant allele carriers of MTHFR A1289C had 4% lower LINE-1 methylation (Ratio 0.96, 95% CI 0.93-0.98), while variant allele carriers of MTR A2756G (Ratio 1.03, 95% CI 1.01-1.06) and MTRR A66G (Ratio 1.03, 95% CI 1.01-1.06) had 3% higher LINE-1 methylation, compared to those carrying the more common genotypes of these SNPs. DNA methylation of LINE-1 elements in histologically normal breast tissues is influenced by polymorphisms in genes in the one-carbon metabolism pathway. Future studies are needed to investigate the sociodemographic, environmental and additional genetic determinants of DNA methylation in breast tissues and the impact on breast cancer susceptibility.

Relationships among folate, alcohol consumption, gene variants in one-carbon metabolism and p16INK4a methylation and expression in healthy breast tissues.

p16(INK4a) is a tumor suppressor gene, frequently hypermethylated in breast cancer; this epigenetic silencing of p16(INK4a) occurs early in carcinogenesis. The risk factors and functional consequences of p16(INK4a) methylation are unknown. Alcohol consumption, a breast cancer risk factor, impedes folate metabolism and may thereby alter gene methylation since folate plays a pivotal role in DNA methylation. In a cross-sectional study of 138 women with no history of breast cancer who underwent reduction mammoplasty, we studied breast cancer risk factors, plasma and breast folate concentrations, variation in one-carbon metabolism genes, p16(INK4a) promoter methylation and P16 protein expression. Logistic regression was used to estimate multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI). p16(INK4a) methylation was negatively correlated with P16 expression (r = -0.28; P = 0.002). Alcohol consumption was associated with lower breast folate (P = 0.03), higher p16(INK4a) promoter methylation (P = 0.007) and less P16 expression (P = 0.002). Higher breast folate concentrations were associated with lower p16(INK4a) promoter methylation (P = 0.06). Genetic variation in MTRR (rs1801394) and MTHFD1 (rs1950902) was associated with higher p16 (INK4a) promoter methylation (OR = 2.66, 95% CI: 1.11-6.42 and OR = 2.72, 95% CI: 1.12-6.66, respectively), whereas variation in TYMS (rs502396) was associated with less P16 protein expression (OR = 0.22, 95% CI: 0.05-0.99). Given that this is the first study to indicate that alcohol consumption, breast folate and variation in one-carbon metabolism genes are associated with p16(INK4a) promoter methylation and P16 protein expression in healthy tissues; these findings require replication.

Natrelle round silicone breast implants: Core Study results at 10 years.

BACKGROUND: Allergan's Natrelle round silicone-filled breast implants were approved by the U.S. Food and Drug Administration in 2006 based on interim results from the Core Study; final 10-year study results are now available. METHODS: Seven hundred fifteen subjects were implanted with smooth and Biocell textured Natrelle round silicone implants and attended clinic visits at 0 to 4 weeks, 6 months, 1 year, and annually through 10 years. Approximately one-third of subjects underwent magnetic resonance imaging at years 1, 3, 5, 7, and 9 to assess rupture. RESULTS: Complication rates showed modest increases over the previously published 6-year rates. The Kaplan-Meier capsular contracture rate was 18.9 percent for augmentation, 28.7 percent for revision-augmentation, and 24.6 percent for reconstruction. Among augmentation subjects, capsular contracture was significantly lower (p = 0.023) for submuscular (15.7 percent) versus subglandular (26.3 percent) placement. The overall rupture rate in the magnetic resonance imaging cohort was 13.0 percent for subjects and 7.7 percent for implants. By the end of the study, 81.8 percent of augmentation subjects still had an original implant in place. Using a five-point scale, 94.2 percent of augmentation, 83.8 percent of revision-augmentation, and 90.7 percent of reconstruction subjects reported being satisfied or definitely satisfied with their implants. Significant improvement over baseline was also seen in overall breast satisfaction and satisfaction with breast size, shape, feel, and how well they matched. CONCLUSION: The 10-year data from the Natrelle Core Study, which can guide surgeons and patients in decision-making, demonstrate safety and high levels of patient satisfaction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Evaluating long-term outcomes following nipple-sparing mastectomy and reconstruction in the irradiated breast.

BACKGROUND: Although it is well established that reconstruction of the irradiated breast is associated with diminished cosmetic results and more frequent complications, little is known about the specific effects of radiation therapy on the reconstructive outcomes after nipple-sparing mastectomy. METHODS: Patients who had nipple-sparing mastectomy and had either previous radiation therapy for breast-conservation therapy or postmastectomy radiation therapy were reviewed. Patient demographics, reconstructive details, and postoperative outcomes were analyzed. Patient photographs were used to evaluate aesthetic parameters. Fisher's exact and t tests were used for comparison of groups, with a value of p < 0.05 considered significant. RESULTS: Eighteen patients were identified as having nipple-sparing mastectomy either after breast-conservation therapy (72.2 percent) or before postmastectomy radiation therapy (27.8 percent), with an average follow-up of 3 years. First-stage complications occurred in six patients (33.3 percent). Nipple position was classified as high-riding in 55.6 percent of patients. Average time to revision was 13.3 months. Most common revisions were for correction of malposition (27.8 percent), capsular contracture (16.7 percent), and high-riding nipple (22.4 percent). Capsular contracture occurred more commonly in patients who needed postmastectomy radiation therapy compared with those who had previously undergone breast-conservation therapy (40 percent versus 7.8 percent). Maintenance of reconstruction occurred in 88.9 percent patients, with eventual implant loss occurring in two patients (11.1 percent). CONCLUSIONS: Nipple-sparing mastectomy and implant reconstruction should be approached cautiously in the setting of radiation therapy. When early complications are present, significant morbidity may occur. Late revision surgery is common in this subset of patients. Implant malposition and a high-riding nipple occur most frequently. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

A prospective study on lipoaugmentation of the breast.

BACKGROUND: The current standard for breast augmentation involves placement of an implant. As an alternative, surgeons have been exploring breast augmentation with autologous tissue in the form of injectable fat. OBJECTIVES: The authors explore the efficacy and safety of lipoaugmentation of the breast, with specific interest in volume changes, fat retention, overall aesthetic improvement, and patient satisfaction. METHODS: Direct measurements, 2- and 3-dimensional images, mammograms, and magnetic resonance imaging (MRI) were obtained preoperatively from 10 consecutive patients undergoing augmentation mammaplasty with autologous fat transfer. These measurements were repeated 1 year postoperatively. Postoperative photo imaging was conducted at 3-month intervals for 1 year. Efficacy was evaluated by determining the volume of fat retention 1 year after the procedure with 3-dimensional imaging, standard breast MRI volume measurements, and subjective aesthetic comparisons. RESULTS: The average amount of fat injected was 236 cc (90-324; SD, 69.8) in the right breast and 250 cc (90-300; SD, 65.1) in the left. The mean volume change based on 3-dimensional imaging was 85.1 cc (36% retention) for the right breast and 98.1 cc (39.2% retention) for the left. The mean volume change based on MRI measurements was 30.0 cc (39.8% change) on the right and 29.3 cc (38.1% change) on the left. Blinded observers found substantial improvement in 1 patient (10%), moderate improvement in 5 patients (50%), and minimal to no improvement in 4 (40%). Overall patient satisfaction was high, as measured by the abbreviated BREAST-Q. Radiologic abnormalities and artifacts were common and required additional imaging. CONCLUSIONS: Objective breast enlargement in this study was modest but yielded disproportionately high subjective patient satisfaction reports. LEVEL OF EVIDENCE: 2.

Analyzing implant movement with tabbed and nontabbed expanders through the process of two-stage breast reconstruction.

BACKGROUND: Tabbed tissue expanders have the potential benefit of less migration during the expansion process, which may allow for more predictable outcomes. Despite this theoretical benefit, no study has critically evaluated the proposed advantage as compared with traditional nontabbed expanders. Therefore, the authors photographically analyzed the migration and movement of tabbed and nontabbed expanders throughout the reconstructive process. METHODS: The authors performed a retrospective review of patients who underwent two-stage expander-to-implant reconstruction from 2010 to 2012. Standardized frontal photographs were used for analysis. Adobe Photoshop was used to measure the relative movement of each patient's expander from insertion until immediately before implant exchange and after implant exchange. RESULTS: Forty-four breasts were analyzed. Migration was reduced significantly in all four directions for both the tissue expander and permanent implant stages of reconstruction. Medial, lateral, superior, and inferior migration of the tissue expander in the tabbed cohort was reduced by 59.5 percent (p = 0.001), 48.3 percent (p = 0.004), 53.4 percent (p = 0.0005), and 73.4 percent (p < 0.0001), respectively, compared with the nontabbed cohort. Likewise, medial, lateral, superior, and inferior migration of the permanent implant in the tabbed cohort was reduced by 44.3 percent (p = 0.049), 73.7 percent (p < 0.0001), 67.7 percent (p = 0.0008), and 61.0 percent (p = 0.003), respectively. CONCLUSIONS: Two-stage implant reconstruction allows for precision in implant placement after an appropriately placed expander. Tabbed expanders appear to maintain better positioning on the chest wall compared with nontabbed expanders during the expansion process, and may allow for more precise mound creation with the permanent implant. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Reduction mammaplasty and mastopexy in previously irradiated breasts.

BACKGROUND: Little data exist on the safety of elective breast surgery following breast conservation therapy. OBJECTIVES: The authors evaluate their experience performing reduction mammaplasties and mastopexies in previously irradiated breasts. METHODS: A retrospective chart review was conducted of all reduction mammaplasties and mastopexies in previously irradiated breasts performed by the 2 senior authors (MYN and SLS) from 1995 to 2012 (n = 18). Patient records were analyzed for demographics, perioperative and postoperative details, and complications. RESULTS: During the study period, 12 reduction mammaplasties and 6 mastopexies were performed on breasts previously treated with breast conservation therapy. The average study participant age was 49.5 years, and average body mass index was 29. Average preoperative bra cup size was D/DD. One patient was a former smoker; 17 were nonsmokers. Eleven of the 18 patients had been previously treated with chemotherapy; average time between radiation therapy and surgery was 2.5 years. Average specimen weight in the 12 reduction mammaplasties was 623 g. Twenty-two percent (n = 4) of patients experienced a total of 5 minor complications; none required a return to the operating room. One patient (6%) experienced a major complication resulting in approximately 50% loss of breast tissue, which was reconstructed with a latissimus dorsi musculocutaneous flap. Seventeen patients (94%) had successful outcomes with preoperative goals achieved. CONCLUSIONS: In the previously irradiated breast, reduction mammaplasty and mastopexy should be approached with extra caution, but the surgeries may still be safely and successfully performed. LEVEL OF EVIDENCE: 4.