ASO Author Reflections: Toward Individualized Management of Heterogenous Mixed Invasive Ductolobular Breast Cancers.

Mixed invasive ductolobular breast cancer (MIDLC) is a rare breast cancer with varying lobular and ductal components. Characteristics, management, and outcomes of MIDLC are not well understood due to the rarity of the cancer and the lack of uniform diagnostic criteria and reporting. There is a need for better understanding and individualized management of this heterogeneous spectrum of breast cancers.

Lobular-Like Features and Outcomes of Mixed Invasive Ductolobular Breast Cancer (MIDLC): Insights from 54,403 Stage I-III MIDLC Patients.

BACKGROUND: Mixed invasive ductolobular breast cancer (MIDLC) is a rare histological subtype of breast cancer (BC), with components of both invasive ductal cancer (IDC) and invasive lobular cancer (ILC). Its clinicopathological features and outcomes have not been well characterized. METHOD: The National Cancer Database 2010-2017 was reviewed to identify women with stage I-III BCs. Univariate analysis was performed using Chi-square or Wilcoxon rank-sum tests and multivariable analysis with logistic regression to predict surgical decisions. Survival was assessed using multivariable Cox proportional hazards regression analysis. RESULTS: We identified 955,828 women with stage I-III BCs (5.7% MIDLC, 10.3% ILC, and 84.0% IDC). MIDLC was more like ILC than IDC in terms of multicentricity (14.2% MIDLC, 13.0% ILC, 10.0% IDC), hormone receptor positivity (96.6% MIDLC, 98.2% ILC, 81.2% IDC), and use of neoadjuvant chemotherapy (NAC; 5.8% MIDLC, 5.2% ILC, 10.8% IDC). 744,607 women underwent upfront surgery. The mastectomy rates were 42.3% for MIDLC, 46.5% for ILC, and 33.3% for IDC (all p < 0.001). With 5.5 years of median follow-up, the adjusted overall survival in the upfront surgery hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) biological subgroup was better in MIDLC (hazard ratio 0.88, p < 0.001) and ILC (hazard ratio 0.91, p < 0.001) than in IDC. Like ILC, MIDLC also had a lower pathological complete response to NAC than IDC (12.3% MIDLC, 7.3% ILC, 28.6% IDC). CONCLUSIONS: MIDLC displays a mixed pattern of characteristics favoring features of ILC compared with IDC, with favorable 5-year overall survival compared with IDC within the HR+/HER2- subtype who underwent upfront surgery.

Immune cells are increased in normal breast tissues of BRCA1/2 mutation carriers.

PURPOSE: Breast cancer risk is elevated in pathogenic germline BRCA 1/2 mutation carriers due to compromised DNA quality control. We hypothesized that if immunosurveillance promotes tumor suppression, then normal/benign breast lobules from BRCA carriers may demonstrate higher immune cell densities. METHODS: We assessed immune cell composition in normal/benign breast lobules from age-matched women with progressively increased breast cancer risk, including (1) low risk: 19 women who donated normal breast tissue to the Komen Tissue Bank (KTB) at Indiana University Simon Cancer Center, (2) intermediate risk: 15 women with biopsy-identified benign breast disease (BBD), and (3) high risk: 19 prophylactic mastectomies from women with germline mutations in BRCA1/2 genes. We performed immunohistochemical stains and analysis to quantitate immune cell densities from digital images in up to 10 representative lobules per sample. Median cell counts per mm2 were compared between groups using Wilcoxon rank-sum tests. RESULTS: Normal/benign breast lobules from BRCA carriers had significantly higher densities of immune cells/mm2 compared to KTB normal donors (all p < 0.001): CD8 + 354.4 vs 150.9; CD4 + 116.3 vs 17.7; CD68 + 237.5 vs 57.8; and CD11c + (3.5% vs 0.4% pixels positive). BBD tissues differed from BRCA carriers only in CD8 + cells but had higher densities of CD4 + , CD11c + , and CD68 + immune cells compared to KTB donors. CONCLUSIONS: These preliminary analyses show that normal/benign breast lobules of BRCA mutation carriers contain increased immune cells compared with normal donor breast tissues, and BBD tissues appear overall more similar to BRCA carriers.

Towards defining morphologic parameters of normal parous and nulliparous breast tissues by artificial intelligence.

BACKGROUND: Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described. METHODS: Using validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors ≤ 45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean "capillary" area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fisher's exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [recent birth: ≤ 5 years versus remote birth: > 5 years]) using multivariable regression models. RESULTS: Normal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p < 0.001). Differences in TDLU counts and average acini size persisted for > 5 years postpartum, whereas increases in immune cells were most marked ≤ 5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration. CONCLUSIONS: Our study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.

Serum hormone levels and normal breast histology among premenopausal women.

PURPOSE: Breast terminal duct lobular units (TDLUs) are the main source of breast cancer (BC) precursors. Higher serum concentrations of hormones and growth factors have been linked to increased TDLU numbers and to elevated BC risk, with variable effects by menopausal status. We assessed associations of circulating factors with breast histology among premenopausal women using artificial intelligence (AI) and preliminarily tested whether parity modifies associations. METHODS: Pathology AI analysis was performed on 316 digital images of H&E-stained sections of normal breast tissues from Komen Tissue Bank donors ages ≤ 45 years to assess 11 quantitative metrics. Associations of circulating factors with AI metrics were assessed using regression analyses, with inclusion of interaction terms to assess effect modification. RESULTS: Higher prolactin levels were related to larger TDLU area (p < 0.001) and increased presence of adipose tissue proximate to TDLUs (p < 0.001), with less significant positive associations for acini counts (p = 0.012), dilated acini (p = 0.043), capillary area (p = 0.014), epithelial area (p = 0.007), and mononuclear cell counts (p = 0.017). Testosterone levels were associated with increased TDLU counts (p < 0.001), irrespective of parity, but associations differed by adipose tissue content. AI data for TDLU counts generally agreed with prior visual assessments. CONCLUSION: Among premenopausal women, serum hormone levels linked to BC risk were also associated with quantitative features of normal breast tissue. These relationships were suggestively modified by parity status and tissue composition. We conclude that the microanatomic features of normal breast tissue may represent a marker of BC risk.

Sexual Well-Being After Nipple-Sparing Mastectomy: Does Preservation of the Nipple Matter?

INTRODUCTION: The primary aim of this study was to evaluate patient-reported outcome measures in patients undergoing mastectomy with and without breast reconstruction (immediate or delayed) with and without nipple preservation. METHODS: All female patients undergoing mastectomy between 2011 and 2015 at Mayo Clinic Rochester were identified and were mailed the BREAST-Q survey. Breast satisfaction, psychosocial well-being, and sexual well-being were evaluated and compared by surgery type using Wilcoxon rank-sum tests for univariate analysis and linear regression for multivariable analysis adjusting for potential confounders. RESULTS: Of 1547 patients, 771 completed the BREAST-Q survey (response rate 50%). Of these 771 respondents, 237 (31%) did not have reconstruction, 198 (26%) had nipple-sparing mastectomy with reconstruction (NSM), and 336 (44%) had skin-sparing mastectomy with reconstruction (SSM) ± nipple-areolar complex (NAC) reconstruction (via surgery ± tattoo). Patients with breast reconstruction had consistently higher BREAST-Q scores versus those without. Comparing NSM with all SSMs, there was no difference in satisfaction with breasts (mean 71.8 vs. 70.2, p = 0.21) or psychosocial well-being (mean 81.9 vs. 81.3, p = 0.47); however, sexual well-being was significantly higher in the NSM group on univariate (mean 64.5 vs. 58.0, p = 0.002) and multivariable (ß = -4.69, p = 0.03) analysis. Sexual well-being scores were similar for NSM and the SSM subgroups with any type of NAC reconstruction. CONCLUSIONS: This study demonstrates that NSM positively impacts patient sexual well-being after breast reconstruction compared with SSM, particularly SSM without nipple reconstruction or tattoo. SSM with any type of NAC reconstruction achieved similar satisfaction and sexual well-being to those undergoing NSM.

Node Positivity Among Sonographically Suspicious but FNA-Negative Axillary Nodes.

BACKGROUND: Fine needle aspiration (FNA) of sonographically suspicious axillary lymph nodes is helpful to clinically stage patients and guide consideration of neoadjuvant therapy in breast cancer. However, data are limited for suspicious nodes that are FNA negative. Our goal is to compare the frequency of node positivity between patients with negative axillary ultrasound (AUSneg) versus suspicious AUS with negative FNA (FNAneg). METHODS: With IRB approval, we identified all clinically node-negative (cN0) patients with invasive breast cancer treated with upfront surgery at our tertiary care center between 2016 and 2021. AUS is routinely performed with FNA of suspicious lymph node(s). We compared clinicopathologic characteristics and nodal positivity rates between AUSneg and FNAneg groups. RESULTS: A total of 1580 cN0 patients with invasive breast cancer were analyzed, including 1240 AUSneg and 340 FNAneg patients. The FNAneg group was younger (median age 59.7 years versus 63.5 years, p < 0.001) and had higher clinical T (cT) category (29.1% versus 21.7% with cT2-cT4 disease, p = 0.005). Final axillary pathologic node positivity did not differ significantly between the AUSneg and FNAneg groups (16.5% versus 19.1%, p = 0.25). Among FNAneg patients, 58/340 (17.1%) had a clip placed, with retrieval confirmed in 28/58 (48.3%). Of the 28 retrieved clipped nodes, 27 were sentinel nodes. Final pathologic nodal status (pN+%) did not differ between patients in whom retrieval of the clipped node was confirmed versus not confirmed (28.6% versus 16.7%, p = 0.28). CONCLUSIONS: Both patients with sonographically suspicious node(s) and negative FNA and patients with negative AUS have a similarly low chance of positive nodes. Additionally, routine targeted excision of FNA-negative clipped nodes is not warranted.

Surgical Management of Axilla Following Neoadjuvant Endocrine Therapy.

BACKGROUND: Randomized clinical trials support deescalation of axillary surgery in breast cancer patients with low-volume axillary disease treated with a surgery-first approach. However, few data exist to guide axillary surgery following neoadjuvant endocrine therapy (NET). Therefore, we evaluated the extent and outcomes of axillary surgery in a contemporary cohort of NET patients, a treatment approach that has become particularly relevant during the coronavirus disease-19 (COVID-19) pandemic. PATIENTS AND METHODS: We identified invasive breast cancer patients treated with NET between October 2008 and November 2019. Patients presenting with stage IV disease or recurrent disease were excluded. Statistical analyses were performed using chi-square, Fisher's exact, and Wilcoxon rank-sum tests. RESULTS: 194 invasive breast cancers in 186 patients (median age 66 years) were evaluated; 81 patients had breast-conserving surgery (BCS), while 113 underwent mastectomy. Eighty-four patients (43.3%) were biopsy-proven cN+ with 4/84 (4.8%) ypN0 following NET. Among cN+ patients, 14 (16.7%) had sentinel lymph node biopsy (SLNB) only, 27 (32.1%) had SLNB + axillary lymph node dissection (ALND), and 43 (51.2%) had ALND. Among 110 cN0 patients, 99 had axillary surgery with 28/99 (28.3%) ypN+: SLNB in 83 (75.5%), SLNB+ALND in 14 (12.7%), and ALND in 2 (1.8%). Among all ypN+ patients, 23/108 (21.3%) had SLNB alone: 18/43 (41.9%) of BCS and 5/65 (7.7%) mastectomy patients (p < 0.001). After median follow-up of 35 months, no regional recurrences were observed. CONCLUSIONS: Among biopsy-proven cN+ NET patients, we observed deescalation of axillary surgery in selected patients, despite a low nodal pathologic complete response (pCR) rate, without nodal recurrences. These data suggest that patients with low-volume axillary disease treated with NET may be managed similarly to patients treated with a surgery-first approach.

Primary tumor resection in patients with stage IV breast cancer: 10-year experience.

The role of surgery in the management of stage IV breast cancer is controversial. Existing studies in Stage IV breast cancer have not closely evaluated the role of patient response to induction systemic therapy (IST) in its relationship to survival outcomes. We identified all patients with a diagnosis of de novo stage IV breast cancer who underwent surgery of their primary tumor from January 2008 to December 2018. Patients were grouped according to their response in the primary disease site into progression (progressive primary disease) or no progression (nonprogressive primary; comprising complete, partial and stable response). We identified a total of 45 stage IV breast cancer patients who underwent operative intervention of their primary breast tumor. Prior to surgical intervention, progression in the primary site during IST was identified in 13/42 patients (31%), of whom four patients also had progression in the distant disease. The 5-year survival was higher in the nonprogressive primary (74%) than the progressive primary disease group (52%) which did not reach statistical significance (p = 0.08). Age, pathologic tumor size, clinical nodal status, number of positive lymph nodes, and distant disease response to systemic therapy were significantly associated with survival. In this single institution experience, select patients with stage IV breast cancer at initial diagnosis who underwent resection of the primary tumor following systemic therapy achieved favorable overall and distant progression-free survival. Surgery is reasonable to consider for local palliation or in selected patients who have excellent response to systemic therapy and good performance status.

Cytotoxic T cell depletion with increasing epithelial abnormality in women with benign breast disease.

PURPOSE: We quantified cytotoxic T cells in nonmalignant breast tissues from women with and without subsequent breast cancer to assess evidence of whether immunosurveillance may be suppressed prior to tumor development. METHODS: We used an age-matched set of breast tissues from women with benign breast disease (BBD) who subsequently developed breast cancer (BBD with later BC), women with BBD who remained cancer free (BBD cancer-free), and normal Komen Tissue Bank (KTB) tissue donors (KTB controls). We evaluated terminal duct lobular units (lobules) for degree of epithelial abnormality and density of dual-positive CD8/CD103 T cells, as CD103+ cells are thought to be a subset of CD8+ cytotoxic T cells located primarily in the intraepithelial compartment. RESULTS: In 10 sets of age-matched women, 256 breast lobules were studied: 85 in BBD women with later BC, 85 in BBD cancer-free women, and 86 in KTB donors. The majority of all lobules were histologically normal (N = 143, 56%), with 65 (25%) nonproliferative fibrocystic change, and 48 (19%) proliferative epithelial change (with or without atypia). In BBD women with later BC, median CD8+/CD103+ cell density was 39.6, 31.7, and 10.5 cells/mm2 (p = 0.002) for normal, nonproliferative, and proliferative lobules. In BBD cancer-free women, median CD8+/CD103+ cell density values were 46.7, 14.3, and 0 cells/mm2 (p = 0.004) respectively. In KTB donors, CD8+/CD103+ cell density was not significantly different across the lobule types (medians 0, 5.8, 10.7, p = 0.43). CONCLUSION: In women with BBD, breast lobules with increasing epithelial abnormality show significant decreases in cytotoxic T cells as measured by CD8/CD103 staining, suggesting that impaired immunosurveillance may be a component of the earliest stages of breast cancer development.

Breast Reconstruction in the Setting of Stage 4 Breast Cancer: Is It Worthwhile?

BACKGROUND: The role of reconstruction after primary tumor surgery for metastatic breast cancer remains controversial. This report describes the outcomes for patients undergoing mastectomy with and without reconstruction in the setting of de novo stage 4 breast cancer. METHODS: Using a prospectively maintained institutional breast surgery database, this study identified all patients who presented with de novo stage 4 breast cancer from January 2008 to December 2018. Patients were included if they had undergone mastectomy with or without reconstruction. Patient, surgical characteristics, and survival outcomes were abstracted and analyzed. RESULTS: The study identified 29 patients: 8 patients (28%) who underwent reconstruction (R) and 21 patients (72%) who did not (NR). Complete clinical response to induction systemic therapy was more frequent among patients in the R group than among those in the NR group for the primary disease (50% in R, 5% in NR), and to a lesser degree for distant disease (63% in R, 39% in NR). No difference in complication rates between the two groups was identified [n = 1 (13%) in R; n = 2 (10%) in NR; p = 1.0]. Overall survival from surgery was longer in the R group (100% at 2 and 5 years) than in the NR group [85%; 95% confidence interval (CI), 68-100% at 2 years vs 50%; 95% CI 27-91% at 5 years] (p = 0.046). CONCLUSION: Breast reconstruction after mastectomy may be reasonable to consider for appropriately selected patients with de novo stage 4 breast cancer who have excellent responses to systemic therapy and anticipated durable survival.

Intraoperative Pathologic Margin Analysis and Re-Excision to Minimize Reoperation for Patients Undergoing Breast-Conserving Surgery.

BACKGROUND: Reoperation rates following breast-conserving surgery (BCS) range from 10 to 40%, with marked surgeon and institutional variation. OBJECTIVE: The aim of this study was to identify factors associated with intraoperative margin re-excision, evaluate for any differences in local recurrence based on margin re-excision and determine reoperation rates with use of intraoperative margin analysis. PATIENTS AND METHODS: We analyzed consecutive patients with ductal carcinoma in situ (DCIS) or invasive breast cancer who underwent BCS at our institution between 1 January 2005 and 31 December 2016. Routine intraoperative frozen section margin analysis was performed and positive or close margins were re-excised intraoperatively. Univariate analysis was used to compare margin status and the Kaplan-Meier method was used to compare recurrence. Multivariable logistic regression was utilized to analyze factors associated with re-excision. RESULTS: We identified 3201 patients who underwent BCS-688 for DCIS and 2513 for invasive carcinoma. Overall, 1513 (60.2%) patients with invasive cancer and 434 (63.1%) patients with DCIS had close or positive margins that underwent intraoperative re-excision. Margin re-excision was associated with larger tumor size in both groups. The permanent pathology positive margin rate among all patients was 1.2%, and the 30-day reoperation rate for positive margins was 1.1%. Five-year local recurrence rates were 0.6% and 1.2% for patients with DCIS and invasive cancer, respectively. There was no difference in recurrence between patients with and without intraoperative margin re-excision (p = 0.92). CONCLUSION: Both DCIS and invasive carcinoma had similar rates of intraoperative margin re-excision. Although intraoperative margin re-excision was common, the reoperation rate was extremely low and there was no difference in recurrence between those with or without intraoperative re-excision.

Workload Differentiates Breast Surgical Procedures: NSM Associated with Higher Workload Demand than SSM.

BACKGROUND: Breast surgery has evolved with more focus on improving cosmetic outcomes, which requires increased operative time and technical complexity. Implications of these technical advances in surgery for the surgeon are unclear, but they may increase intraoperative demands, both mentally and physically. We prospectively evaluated mental and physical demand across breast surgery procedures, and compared surgeon ergonomic risk between nipple-sparing (NSM) and skin-sparing mastectomy (SSM) using subjective and objective measures. METHODS: From May 2017 to July 2017, breast surgeons completed modified NASA-Task Load Index (TLX) workload surveys after cases. From January 2018 to July 2018, surgeons completed workload surveys and wore inertial measurement units to evaluate their postures during NSM and SSM cases. Mean angles of surgical postures, ergonomic risk, survey items, and patient factors were analyzed. RESULTS: Procedural duration was moderately related to surgeon frustration, mental and physical demand, and fatigue (p < 0.001). NSMs were rated 23% more physically demanding (M = 13.3, SD = 4.3) and demanded 28% more effort (M = 14.4, SD = 4.6) than SSMs (M = 10.8, SD = 4.7; M = 11.8, SD = 5.0). Incision type was a contributing factor in workload and procedural difficulty. Left arm mean angle was significantly greater for NSM (M = 30.1 degrees, SD = 6.6) than SSMs (M = 18.2 degrees, SD = 4.3). A higher musculoskeletal disorder risk score for the trunk was significantly associated with higher surgeon physical workload (p = 0.02). CONCLUSION: Nipple-sparing mastectomy required the highest surgeon-reported workload of all breast procedures, including physical demand and effort. Objective measures identified the surgeons' left upper arm as being at the greatest risk for a work-related musculoskeletal disorder, specifically from performing NSMs.

Single-Stage Direct-to-Implant Breast Reconstruction: A Comparison Between Subpectoral Versus Prepectoral Implant Placement.

BACKGROUND: Single-stage direct-to-implant (DTI) breast reconstruction can offer several potential benefits. Subpectoral DTI reconstruction can present with animation deformity and pectoralis muscle spasm. To potentially avoid these complications, surgeons have attempted prepectoral placement for DTI; however, the benefits of this approach are mostly unknown. We evaluated the outcomes of DTI between prepectoral and subpectoral placement. METHODS: This was a retrospective review of patients who underwent immediate DTI breast reconstruction (prepectoral vs subpectoral) between 2011 and 2018. Demographics, clinical characteristics, complications, and patient-reported outcomes (BREAST-Q) were compared. RESULTS: Thirty-three patients (55 breasts) underwent prepectoral DTI, and 42 patients (69 breasts) underwent subpectoral DTI. Demographics were similar among groups. The number of breasts with preoperative ptosis lower than grade 2 was not significantly different between groups (29.1% vs 26.1%; P = 0.699). Median follow-up was 20.3 and 21 months in the prepectoral and subpectoral groups, respectively. Average mastectomy weight was 300 g (180-425 g) and 355 g (203-500 g). Average implant size was 410 cc (330-465 cc) and 425 cc (315-534 cc) in the prepectoral and subpectoral groups, respectively. Alloderm was used in all reconstructions. Total numbers of complications were 4 (7.2%) and 8 (11.6%) in the prepectoral and subpectoral groups, respectively (P = 0.227). BREAST-Q demonstrated mean patient satisfaction was high and similar among groups (75 and 73.9, P = 0.211). CONCLUSIONS: Based on these results, we believe prepectoral DTI is safe, reliable, and a promising reconstructive option for selected patients, with equivalent results to other reconstructive options. Our present treatment recommendations are for patients who wish to maintain the same breast size and have minimal or no breast ptosis.

Bioinformatics and DNA-extraction strategies to reliably detect genetic variants from FFPE breast tissue samples.

BACKGROUND: Archived formalin fixed paraffin embedded (FFPE) samples are valuable clinical resources to examine clinically relevant morphology features and also to study genetic changes. However, DNA quality and quantity of FFPE samples are often sub-optimal, and resulting NGS-based genetics variant detections are prone to false positives. Evaluations of wet-lab and bioinformatics approaches are needed to optimize variant detection from FFPE samples. RESULTS: As a pilot study, we designed within-subject triplicate samples of DNA derived from paired FFPE and fresh frozen breast tissues to highlight FFPE-specific artifacts. For FFPE samples, we tested two FFPE DNA extraction methods to determine impact of wet-lab procedures on variant calling: QIAGEN QIAamp DNA Mini Kit ("QA"), and QIAGEN GeneRead DNA FFPE Kit ("QGR"). We also used negative-control (NA12891) and positive control samples (Horizon Discovery Reference Standard FFPE). All DNA sample libraries were prepared for NGS according to the QIAseq Human Breast Cancer Targeted DNA Panel protocol and sequenced on the HiSeq 4000. Variant calling and filtering were performed using QIAGEN Gene Globe Data Portal. Detailed variant concordance comparisons and mutational signature analysis were performed to investigate effects of FFPE samples compared to paired fresh frozen samples, along with different DNA extraction methods. In this study, we found that five times or more variants were called with FFPE samples, compared to their paired fresh-frozen tissue samples even after applying molecular barcoding error-correction and default bioinformatics filtering recommended by the vendor. We also found that QGR as an optimized FFPE-DNA extraction approach leads to much fewer discordant variants between paired fresh frozen and FFPE samples. Approximately 92% of the uniquely called FFPE variants were of low allelic frequency range (< 5%), and collectively shared a "C > T|G > A" mutational signature known to be representative of FFPE artifacts resulting from cytosine deamination. Based on control samples and FFPE-frozen replicates, we derived an effective filtering strategy with associated empirical false-discovery estimates. CONCLUSIONS: Through this study, we demonstrated feasibility of calling and filtering genetic variants from FFPE tissue samples using a combined strategy with molecular barcodes, optimized DNA extraction, and bioinformatics methods incorporating genomics context such as mutational signature and variant allelic frequency.

Impact of short-term low-dose tamoxifen on molecular breast imaging background parenchymal uptake: a pilot study.

BACKGROUND: High background parenchymal uptake (BPU) on molecular breast imaging (MBI) has been identified as a breast cancer risk factor. We explored the feasibility of offering a short-term intervention of low-dose oral tamoxifen to women with high BPU and examined whether this intervention would reduce BPU. METHODS: Women with a history of high BPU and no breast cancer history were invited to the study. Participants had an MBI exam, followed by 30 days of low-dose oral tamoxifen at either 5 mg or 10 mg/day, and a post-tamoxifen MBI exam. BPU on pre- and post-tamoxifen MBI exams was quantitatively assessed as the ratio of average counts in breast fibroglandular tissue vs. average counts in subcutaneous fat. Pre-tamoxifen and post-tamoxifen BPU were compared with paired t tests. RESULTS: Of 47 women invited, 22 enrolled and 21 completed the study (10 taking 5 mg tamoxifen, 11 taking 10 mg tamoxifen). Mean age was 47.7 years (range 41-56 years). After 30 days low-dose tamoxifen, 8 of 21 women (38%) showed a decline in BPU, defined as a decrease from the pre-tamoxifen MBI of at least 15%; 11 of 21 (52%) had no change in BPU (within ± 15%); 2 of 21 (10%) had an increase in BPU of greater than 15%. Overall, the average post-tamoxifen BPU was not significantly different from pre-tamoxifen BPU (1.34 post vs. 1.43 pre, p = 0.11). However, among women taking 10 mg tamoxifen, 5 of 11 (45%) showed a decline in BPU; average BPU was 1.19 post-tamoxifen vs. 1.34 pre-tamoxifen (p = 0.005). In women taking 5 mg tamoxifen, 2 of 10 (20%) showed a decline in BPU; average BPU was 1.51 post-tamoxifen vs.1.53 pre-tamoxifen (p = 0.99). CONCLUSIONS: Short-term intervention with low-dose tamoxifen may reduce high BPU on MBI for some patients. Our preliminary findings suggest that 10 mg tamoxifen per day may be more effective than 5 mg for inducing declines in BPU within 30 days. Given the variability in BPU response to tamoxifen observed among study participants, future study is warranted to determine if BPU response could predict the effectiveness of tamoxifen for breast cancer risk reduction within an individual. TRIAL REGISTRATION: ClinicalTrials.gov NCT02979301 . Registered 01 December 2016.

Hyaline fibrous involution of breast lobules: a histologic finding associated with germline BRCA mutation.

We describe the histology and the frequency of a histologic entity that we term "hyaline fibrous involution", which is characterized by symmetric and regular deposition of basal lamina-like periacinar hyaline material in association with atrophic epithelium, in breast samples from patients with either benign breast disease or germline BRCA mutation. Women with germline BRCA mutation (n = 93) who underwent prophylactic mastectomy (BRCA group) were compared to an age-matched sample of women who underwent biopsy for benign breast disease (n = 93). Median age was 45 years (range, 25-72 years). A single H&E section of each subject's benign breast tissue was reviewed. The total number of terminal duct lobular units and the number of terminal duct lobular units with hyaline fibrous involution were recorded for each case. The presence of any hyaline fibrous involution lobules and the within-sample proportion of hyaline fibrous involution lobules relative to total lobules were compared between groups. Presence of any hyaline fibrous involution was significantly more frequent in the BRCA group compared to the benign breast disease group, 47% vs. 15% (p < 0.0001, adjusted for total lobules). In women with any hyaline fibrous involution lobules, these unusual lobules were similarly rare in both groups, with median proportion of hyaline fibrous involution-positive lobules relative to all lobules of 0.03 in BRCA specimens (n = 44) and 0.03 in the benign breast disease group (n = 14). Within the BRCA group, frequency of any hyaline fibrous involution present was significantly higher in the perimenopausal age group (45-55 years: 63%) compared to other age groups (<45 years, 44%; >55 years, 15%; p = 0.05 and p = 0.02, respectively). Increased presence of hyaline fibrous involution in the setting of BRCA mutation suggests that it may represent a pathologic entity, possibly reflecting abnormal involution or an abnormal response to DNA damage.

Outcomes of > 1300 Nipple-Sparing Mastectomies with Immediate Reconstruction: The Impact of Expanding Indications on Complications.

BACKGROUND: The enhanced esthetics and demonstrated oncologic safety of nipple-sparing mastectomy (NSM) in selected patients have resulted in increased rates among patients with locally advanced breast cancer and/or additional risk factors (obesity, prior radiation, surgery). Limited data exist on complication and reconstruction success rates in a contemporary patient cohort with expanded indications for NSM. METHODS: With institutional review board (IRB) approval, patients treated from 2009 to 2017 with NSM were identified from our prospective breast surgery registry. Main outcomes were 30-day complications requiring treatment and 1-year reconstruction failure rates. Risk factors were assessed using logistic regression. RESULTS: We evaluated 1301 breasts in 769 women undergoing NSM for cancer (n = 555) or risk reduction (n = 746) with median age of 48 (range 21-77) years. The overall 30-day complication rate was 7.5% (97/1301 breasts) and declined from 14.8% in 2009 to 6.3% in 2017 (p < 0.001), while the proportion of patients with obesity (p = 0.007) and treated with neoadjuvant chemotherapy (p < 0.001) increased. Prior radiation [odds ratio (OR) 2.35, p = 0.04], recent/current smoking (OR 3.37, p < 0.001), and body mass index (BMI) (OR 1.28 per 5-kg/m2 increase, p = 0.03) significantly increased 30-day complication rates. Reconstruction success at 1 year was 96.7%. Prior radiation (OR 5.65, p < 0.001), axillary surgery (OR 2.55, p = 0.006), and postoperative adjuvant radiation (OR 3.22, p = 0.007) significantly affected 1-year reconstruction failure. CONCLUSION: The 30-day complication rates of NSM decreased, despite broadened indications among higher-risk patients over time. These data confirm a team learning curve with NSM and also demonstrate that the nipple-sparing approach is suitable for appropriately selected higher-risk patients for both risk reduction and cancer treatment.

Two-Staged Implant-Based Breast Reconstruction: A Long-Term Outcome Study in a Young Population.

Background and objectives: Differences in patient anatomy and physiology exist between young and older patients undergoing breast reconstruction after mastectomy. Breast cancer has been described as being more aggressive, more likely to receive radiation, contralateral mastectomy, as well as bilateral reconstruction in young patients. Our purpose is to report long-term experience on two-staged implant-based breast reconstruction (IBR) in young females, with complication sub-analysis based on obesity and adjuvant radiation. Materials and Methods: Retrospective chart review of all consecutive young patients who underwent two-staged IBR at our institution, between 2000 and 2016, was performed. Patients between 15 and 40 years old with least 1-year follow-up were included. Univariate logistic regression models and receiver operating characteristic (ROC) curves were created. Results: Overall 594 breasts met our inclusion criteria. The mean age was 34 years, and the median follow-up was 29.6 months. Final IBR was achieved in 98% of breasts. Overall, 12% of breasts had complications, leading to explantations of 5% of the devices. Adjuvant radiation was followed by higher rates of total device explantations (p = 0.003), while obese patients had higher rates of total complications (p < 0.001). For each point increase in BMI, the odds of developing complications increased 8.1% (p < 0.001); the cutoff BMI to predict higher complications was 24.81 kg/m2. Conclusions: This population demonstrates high successful IBR completion and low explantation rates. These data suggest that obese women and those with planned adjuvant radiation deserve special counseling about their higher risk of complications.