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Basal p53 ChIP-seq peaks in MCF10A cells (after raw data analysis described in Materials in Methods section) ordered by significance of the peak call. Spreadsheet includes (columns left to right) peak locus (Chromosome, start, end), MACS2 significance, closest relevant gene (genes discussed in paper in red type), and original HOMER gene call (if relevant gene differs from called gene).

Supplementary Fig. S1. Basally expressed p53 may have important tumor suppressor targets. Supplementary Fig. S2. Binding targets of basal p53 in MCF10A cells. Supplementary Fig. S3. Exploring the binding targets of basal p53. Supplementary Fig. S4. Wild-type p53 maintains expression of tumor suppressor target genes. Supplementary Fig. S5. Long range chromatin interactions of enhancers with transcriptional start sites of basal p53 targets. Supplementary Fig. S6. Enhancer for PTEN is present in multiple cell types. Supplementary Fig. S7. The binding and regulation of the PTEN locus by basal p53. Supplementary Fig. S8. PTEN-eP53RE is a highly conserved p53 response element in a p53-dependent enhancer. Supplementary Fig. S9. Deletion of endogenous PTEN-eP53RE by CRISPR/Cas9. Supplementary Fig. S10. Depletion of p53 causes a PTEN-eP53RE-dependent decrease in PTEN expression, deletion of PTEN-eP53RE alters some tumor cell phenotypes. Supplementary Table S1. Information on tumor suppressor genes identified as basal p53 targets. Supplementary Table S2. Predicted p53 response elements within basal p53 binding sites using JASPAR. Supplementary Table S3. Chromatin properties of basal p53 binding sites near tumor suppressor genes. Legends for Supplementary Spreadsheets S1-S5. Additional Materials and Methods. References for Supplementary Material.

There is little data exploring the impact of screening mammography on subsequent treatment in the 40-49-year age group with breast cancer. We sought to assess the association between frequency of mammography in young women and extent of surgery and chemotherapy required.An IRB-approved retrospective review was performed of patients diagnosed with breast cancer between ages 40 and 49 years from 1 January 2010 to 19 November 2018 within a single health system. Patients were grouped based on last screening 1-24 months prior to diagnosis (1-24 group),25 months prior to diagnosis (25 group), never screened, and25+ never screened (combination group). Multivariate logistic regression models were used to assess for associations between screening intervals and tumor and nodal stage, chemotherapy use, and extent of surgery.Of 869 patients included for analysis, 20% were never screened, 60% screened 1-24 months, and 19% screened25 months prior to diagnosis. Compared with the 1-24 months group, the never-screened group,25 months group, and combined group were more likely to receive chemotherapy. The never-screened and combined groups were more likely to undergo mastectomy and/or axillary lymph node dissection. Of patients undergoing upfront surgery, the25 months and combined groups were more likely to receive adjuvant chemotherapy, while the never-screened and combined groups were more likely to have nodal disease.Our findings support the initiation of screening mammography at age 40 years to reduce the risk of aggressive treatments for newly diagnosed breast cancers in this group.

Introduction Based on the ACOSOG Z0011 trial, women who undergo breast conservation therapy (BCT) and have limited disease in the axilla on sentinel lymph node (SLN) biopsy do not require axillary lymph node dissection (ALND). In this study we investigate the incidence of ALND in patients undergoing elective mastectomy with limited disease in the axilla to identify how many women may have been spared additional axillary surgery if they chose BCT. Methods All women with invasive breast cancer treated at a single tertiary care breast center from 2010-2018 who were candidates for BCT but elected mastectomy and underwent SLN biopsy were identified through retrospective review of a prospectively maintained database. The primary outcome of interest was the incidence of ALND in women found to have a limited burden of disease in the axilla (1-2 positive SLNs). Results The study population comprised 151 patients with invasive breast cancer eligible for BCT who chose mastectomy. On final pathology, 34 patients had 1-2 positive SLNs, and 16 of these patients underwent completion ALND. These 16 patients out of 151 overall lumpectomy candidates electing mastectomy (10.6%) could have been spared ALND if they did not elect mastectomy. Discussion BCT candidates electing mastectomy have a 10.6% chance of undergoing more extensive axillary surgery than would have been recommended with BCT alone. The increased risk of undergoing additional axillary surgery should be incorporated into the preoperative discussion for patients choosing between BCT and mastectomy.

Anatomic extent of ductal carcinoma in situ (DCIS) may be uncertain in spite of clinical, pathologic, and imaging data. Consequently close/positive margins are common with lumpectomy for DCIS and often lead to a challenge in deciding whether to perform a re-excision or mastectomy.From a single health system, we identified cases of lumpectomy for DCIS with close/positive margins who underwent re-excision for the purpose of constructing a nomogram. In total, 289 patients were available for analysis. The patients were randomly divided into two sets allocating 70% to the modeling and 30% to the validation set. A multivariable logistic regression model was used to estimate the probability of overall positive margin status using multiple clinicopathologic predictors. Nomogram validation included internal tenfold cross-validation, internal bootstrap validation, and external validation for which a concordance index was calculated to assess the external validity.Significant predictors of persistent positive margins from regression modeling included necrosis at diagnosis (non-comedo or comedo); DCIS not associated with calcifications on core biopsy; high-grade DCIS; progesterone receptor positivity; and number of positive margins at initial surgery. When subjected to internal validation, the nomogram achieved an uncorrected concordance index of 0.7332, a tenfold cross-validation concordance index of 0.6795, and a bootstrap-corrected concordance index of 0.6881. External validation yielded an estimated concordance index of 0.7095.Using clinical and pathologic variables from initial diagnosis and surgery for DCIS, this nomogram predicts persistent positive margins with margin re-excision, and may be a valuable tool in surgical decision-making.

Supplementary figure legends

Supplementary Figure 2: Low score PSF does not suppress proliferation. Proliferation curve ofMDA-MB-231 cells treated with 1% Low Score PSF, 1% High Score PSF, or 1% FBS using an MTT assay. (Mean {plus minus} SEM) (n = 5 per group; * p < 0.05; Mann-Whitney test)

Supplementary Figure 3: Comparison of CLIC4 and RYBP mRNA levels in high score and low score treated MDA-MB-231 cells to untreated MDA-MB-231 cells. Real-time PCR of CLIC4 in untreated and high score treated MDA-MB-231 cells normalized to actin. (Mean {plus minus} SEM) (in quadruplicate, ** p < 0.01, Mann-Whitney test). Real-time PCR of RYBP in untreated and low score treated MDA-MB-231 cells normalized to actin. (Mean {plus minus} SEM) (in quadruplicate, ** p < 0.01, Mann-Whitney test).

Purpose: Despite the fact that interstitial fluid (IF) represents a third of our body fluid, it is the most poorly understood body fluid in medicine. Increased IF pressure is thought to result from the increased deposition of extracellular matrix in the affected tissue preventing its reabsorption. In the cancer field, increased rigidity surrounding a cancerous mass remains the main reason that palpation and radiologic examination, such as mammography, are used for cancer detection. While the pressure produced by IF has been considered, the biochemical composition of IF has not been considered in its effect on tumors.Experimental Design: We classified 135 IF samples from bilateral mastectomy patients based on their ability to promote the invasion of breast cancer cells.Results: We observed a wide range of invasion scores. Patients with high-grade primary tumors at diagnosis had higher IF invasion scores. In mice, injections of high-score IF (IFHigh) in a normal mammary gland promotes ductal hyperplasia, increased collagen deposition, and local invasion. In a mouse model of residual disease, IFHigh increased disease progression and promoted aggressive visceral metastases. Mechanistically, we found that IFHigh induces myofibroblast differentiation and collagen production through activation of CLIC4. IFHigh also downregulates RYBP, leading to degradation of p53. Furthermore, in mammary glands of heterozygous p53-mutant knock-in mice, IFHigh promotes spontaneous tumor formation.Conclusions: Our study indicates that IF can increase the deposition of extracellular matrix and raises the provocative possibility that they play an active role in the predisposition, development, and clinical course of sporadic breast cancers. Clin Cancer Res; 23(18); 5446–59. ©2017 AACR.

Purpose Breast Cancer (BC) is the most diagnosed cancer in women; however, through significant research, relative survival rates have significantly improved. Despite progress, there remains a gap in our understanding of BC subtypes and personalized treatments. This manuscript characterized cellular heterogeneity in BC cell lines through scRNAseq to resolve variability in subtyping, disease modeling potential, and therapeutic targeting predictions. Methods We generated a Breast Cancer Single-Cell Cell Line Atlas (BSCLA) to help inform future BC research. We sequenced over 36,195 cells composed of 13 cell lines spanning the spectrum of clinical BC subtypes and leveraged publicly available data comprising 39,214 cells from 26 primary tumors. Results Unsupervised clustering identified 49 subpopulations within the cell line dataset. We resolve ambiguity in subtype annotation comparing expression of Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2 genes. Gene correlations with disease subtype highlighted S100A7 and MUCL1 overexpression in HER2 + cells as possible cell motility and localization drivers. We also present genes driving populational drifts to generate novel gene vectors characterizing each subpopulation. A global Cancer Stem Cell (CSC) scoring vector was used to identify stemness potential for subpopulations and model multi-potency. Finally, we overlay the BSCLA dataset with FDA-approved targets to identify to predict the efficacy of subpopulation-specific therapies. Conclusion The BSCLA defines the heterogeneity within BC cell lines, enhancing our overall understanding of BC cellular diversity to guide future BC research, including model cell line selection, unintended sample source effects, stemness factors between cell lines, and cell type-specific treatment response.

Currently, triple-negative breast cancer (TNBC) has limited therapeutic options beyond chemotherapy and has worse outcomes than other breast cancer subtypes. Initial experience with immune checkpoint blockade for the treatment of TNBC has indicated that modifying the tumor immune response represents a promising direction of investigation. Subsequent studies have led to a deeper understanding of the heterogeneity of this disease and have informed further exploration of numerous potential therapeutic approaches to intervene in the tumor microenvironment (TME).Initial work in this arena has focused on enhanced definition of checkpoints in activation of an adaptive immune response. In this review, we discuss recent efforts that have looked into components of innate immunity to reverse immunosuppressive phenotypes and augment antitumor immune response.Current treatment options for TNBC have been improved with the approval of immune checkpoint inhibitors (ICI) in both advanced and early-stage disease; however, the challenge remains to expand the number of patients that will benefit from immunotherapy. Optimizing the innate immune response represents an opportunity to improve this therapeutic index, and the development of an array of novel agents is underway. Success will depend on precision characterization of the patient TME and selection of ideal combination therapy.

Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced HER2 + breast cancer (BC). Optimal sequencing of treatment (NAC vs. surgery first) is less clear cut in stage I (T1N0) HER2 + BC, where information from surgical pathology could impact adjuvant treatment decisions. Utilizing the NCDB, we evaluated the trend of NAC use compared to upfront surgery in patients with small HER2 + BC. We identified NCDB female patients diagnosed with T1 N0 HER2 + BC from 2010 through 2015. Prevalence ratios (PR) using multivariable robust Poisson regression models were calculated to measure the association between baseline characteristics and the receipt of NAC. Analysis of trends over time was denoted by annual percent change (APC) of NAC versus surgery upfront. Of the 14,949 that received chemotherapy and anti-HER2 therapy during the study period, overall 1281 (8.6%) received NAC and 13,668 (91.4%) received adjuvant treatment. Patients receiving NAC increased annually from 4.2% in 2010 to 17.3% in 2015, with the most rapid increase occurring between years 2013 (8.5%) and 2014 (14.2%). The greatest increase was seen in patients with cT1c tumors with an APC of 37.8% over the study period (95% CI 29.0, 47.3%, p

Neoadjuvant chemotherapy (NAC) is a well-established therapeutic option for patients with locally advanced disease often allowing downstaging and facilitation of breast conserving therapy. With evolution of better targeted treatment regimens and awareness of improved outcomes for significant responders, use of NAC has expanded particularly for triple negative and HER2-positive (HER2+) breast cancer. In this study, we explore utility of neoadjuvant chemotherapy for hormone receptor-positive HER2-negative (HR+ HER2−) patients. Patients with HR+ HER2− breast cancer treated with chemotherapy before or after surgery were identified from 2010 to 2015 in the NCDB. Multivariable regression models adjusted for covariates were used to determine associations within these groups. Among 134,574 patients (clinical stage 2A, 64%; 2B, 21%; 3, 15%), 105,324 (78%) had adjuvant chemotherapy (AC) and 29,250 (22%) received NAC. Use of NAC increased over time (2010–2015; 13.2–19.4% and PR = 1.34 for 2015; p

BACKGROUND Currently, positive margins at lumpectomy contribute to health care cost, patient anxiety, and treatment delay. Multiple technology solutions are being explored with the aim of lowering re-excision rates for breast-conserving surgery (BCS). We examined wide-field optical coherence tomography (WF-OCT), an innovative adjunct intraoperative imaging tool for tissue visualization of margins. METHODS This IRB-approved pilot study included women with invasive or in situ carcinoma scheduled for primary BCS. Lumpectomy specimens and any final/revised margins were imaged by optical coherence tomography immediately prior to standard histological processing. The optical coherence tomography used provided two-dimensional, cross-sectional, real-time depth visualization of the margin widths around excised specimens. A volume of images was captured for 10 × 10 cm tissue surface at high resolution (sub-30 μm) to a depth of 2 mm. Integrated interpretation was performed incorporating final pathology linked with the optical image data for correlation. RESULTS Wide-field optical coherence tomography was performed on 185 tissue samples (50 lumpectomy specimens and 135 additional margin shaves) in 50 subjects. Initial diagnosis was invasive ductal carcinoma (IDC) in 10, ductal carcinoma in situ (DCIS) in 14, IDC/DCIS in 22, invasive lobular carcinoma (ILC) in 2, ILC/DCIS in 1, and sarcoma in 1. Optical coherence tomography was concordant with final pathology in 178/185 tissue samples for overall accuracy of 86% and 96.2% (main specimen alone and main specimen + shave margins). Of seven samples that were discordant, 57% (4/7) were considered close (DCIS

Clinical registries - structured databases of demographic, diagnosis, and treatment information for patients with specific diseases or phenotypes - play vital roles in high-quality retrospective studies, operational planning, and assessment of patient eligibility for research, including clinical trials. However, registries are extremely time and resource intensive to curate. Natural language processing (NLP) can help, but standard NLP methods require specially annotated training sets or the construction of separate models for each of dozens or hundreds of different registry fields, rendering them insufficient for registry curation at scale. Natural language inference (NLI), a specific branch of NLP focused on logical relationships between statements, presents a possible solution, but NLI methods are largely unexplored in the clinical domain outside the realm of conference shared tasks and computer science benchmarks. Here we convert registry curation into an NLI problem, applying five state-of-the-art, pretrained, deep learning based NLI models to clinical, laboratory, and pathology notes to infer information about 43 different breast oncology registry fields. We evaluate the models’ inferences against a manually curated, 7439 patient breast oncology research database. The NLI models show considerable variation in performance, both within and across registry fields. One model, ALBERT, outperforms the others (BART, RoBERTa, XLNet, and ELECTRA) on 22 out of 43 fields. A detailed error analysis reveals that incorrect inferences primarily arise through models’ misinterpretations of temporality--they interpret historical findings as current and vice versa--as well as confusion based on subtle terminology and abbreviation variants common in clinical notes. However, modern NLI methods show promise for increasing the efficiency of registry curation, even when used “out of the box” with no additional training.

Background and Objectives: Local and distant relapse (LR, DR) in breast cancer vary according to its molecular subtypes, with triple-negative breast cancer (TNBC) being the most aggressive. The surgical resection margin width (SRMW) for breast-conserving surgery (BCS) has been intensely debated, especially for the aforementioned subtype. The aim of this study was to examine the impact of SRMW on LR following BCS in TNBC patients. Materials and Methods: We conducted a retrospective study including all patients with TNBC for whom BCS was performed between 2005 and 2014. Results: Final analysis included a total of 92 patients, with a median tumor size of 2.5 cm (range 0–5 cm) and no distant metastasis at the time of diagnosis. A total of 87 patients had received neoadjuvant and/or adjuvant chemotherapy, and all patients had received adjuvant whole-breast radiotherapy. After a median follow-up of 110.7 months (95% CI, 95.23–126.166), there were 5 local recurrences and 8 regional/distant recurrences with an overall LR rate of 5.4%. The risk of LR and DR was similar between groups of patients with several SRMW cut-off values. Conclusions: Our study supports a safe “no ink on tumor” approach for TNBC patients treated with BCS.

Genetic predisposition accounts for 5–10% of all breast cancers (BC) diagnosed. NCCN guidelines help providers identify appropriate candidates for counseling and testing. Concerns about underutilization of genetic testing have spurred interest in broader peri-diagnostic testing. We evaluated surgeon adherence to NCCN guidelines and studied patterns of testing in newly diagnosed BC patients. A total of 397 patients were identified with newly diagnosed BC treated at our institution between 2016 and 2017 with no prior genetic testing. Eligibility for genetic testing based on NCCN criteria, referral, and patient compliance were recorded. In total, 212 of 397 (53%) met NCCN testing criteria. Fifty-nine of 212 (28%) patients went untested despite meeting one or more criteria. Fourteen of 59 (24%) of these were referred but did not comply. Most common criteria for meeting eligibility for testing both in the overall cohort and among missed patients were family history-based. Age > 45 years old and non-Ashkenazi Jewish descent were predictive of missed referral (p

Improved imaging and neoadjuvant chemotherapy (NAT) have led to higher pathologic complete response rates (pCR) in patients with invasive breast cancer. This has questioned the necessity of surgery and axillary lymph node (ALN) dissection in these patients. Prospective clinical trials are implementing extensive core biopsies of the tumor bed of patients with clinical complete response as a means to identify and spare them breast surgery. In addition, it is anticipated that patients with pCR are most likely going to have no or minimal disease in ALN as well. To verify the feasibility of these trials, we performed a pathologic analysis of all our patients who have undergone NAT from 2009 to present. Using pathology data base, we identified 362 patients treated with neoadjuvant chemotherapy followed by surgery. Clinical and pathologic information including gross and microscopic descriptions as well as biomarker status was collected. pCR was 50% for patients with negative ALN pretreatment but only 28% for patients with positive ALN at diagnosis. Despite achieving pCR in the breast, up to 10% of patients with positive ALN and 1% with negative ALN had persistent disease. Eight percent of patients that were presumed to have no ALN disease either clinically and or by imaging were found to have metastatic carcinoma in ALN. The metastases were predominantly (80%)

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare peripheral T-cell lymphoma with approximately 650-700 reported cases worldwide. The incidence, however, is increasing as more practitioners become aware of the diagnosis, and recent studies show that early diagnosis and treatment is critical to improve prognosis. There have been four cases of BIA-ALCL in total reported in the transgender population in the literature. These reported cases were reviewed in detail to determine presentation and management of BIA-ALCL in transgender patients compared to the larger population of BIA-ALCL patients. This review highlights BIA-ALCL in transgender women, a population that is often excluded from breast screening and follow-up. Transgender women may not routinely go through the same post-operative follow-up protocols as patients with breast implants for breast cancer reconstruction and can thus be at risk for delayed recognition and diagnosis. BIA-ALCL is a rare complication of breast implantation, and it is important to counsel all patients undergoing implant placement, including transgender women, on its risk.

Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R-induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER-independent PIK3CA-mutant breast cancer.

Screening mammography reduces breast cancer mortality; however, screening recommendations, ordering, and compliance remain suboptimal and controversies regarding the value of screening persist. We evaluated the influence of screening mammography on the extent of breast cancer treatment. Patients ≥ 40 years of age diagnosed with breast cancer from September 2008 to May 2016 at a single institution were divided into two groups: those with screening 1–24 months prior to diagnosis, and those with screening at 25+ months, including patients with no prior mammography. The association between the two groups and various clinical factors were assessed using logistic regression models. Subgroup analysis was performed based on age groups. Analysis included 1125 patients, 819 (73%) with screening at 1–24 months, and 306 (27%) with screening at 25+ months, including 65 (6%) who never had mammography. Overall, patients in the 25+ months group were more likely to receive chemotherapy [odds ratio (OR) 1.51, p = 0.0040], undergo mastectomy (OR 1.32, p = 0.0465), and require axillary dissection (AD; OR 1.66, p = 0.0045) than those in 1–24 months group. On subgroup analysis, patients aged 40–49 years with no prior mammography were more likely to have larger tumors (p = 0.0323) and positive nodes (OR 4.52, p = 0.0058), undergo mastectomy (OR 3.44, p = 0.0068), undergo AD (OR 4.64, p = 0.0002), and require chemotherapy (OR 2.52, p = 0.0287) than the 1–24 months group. Screening mammography is associated with decreased stage at diagnosis and receipt of less-extensive treatment. This was evident in all groups, including the 40–49 years age group, where controversy exists on whether screening is even necessary.

Rationale and Objectives This study aimed to assess whether different breast cancer subspecialty physicians can be trained to distinguish non-suspicious from suspicious areas of post-lumpectomy specimen margin in patients with breast cancer using optical coherence tomography (OCT) images (a near-infrared based imaging technique) with final histology as the reference standard. Materials and Methods This institutional review board-exempt, Health Insurance Portability and Accountability Act-compliant study was performed on 63 surgically excised breast specimens from 35 female patients, creating a 90-case atlas containing both non-suspicious and suspicious areas for cancer. OCT images of the specimens were performed, providing 6.5–15 µm resolution with tissue visualization 1–2 mm subsurface. From the 90-case atlas, 40 cases were chosen for training and 40 were randomly selected for reader assessment. Three breast imaging radiologists, two pathologists, two breast surgeons, and one non-clinical reader were trained and assessed for ability to distinguish non-suspicious from suspicious findings blinded to clinical data and corresponding histology slides. Duration of training and assessment, sensitivity, specificity, positive predictive value, negative predictive value, and the area under the curve for each reader were calculated as well as averages by subspecialty. Results The average training time was 3.4 hours (standard deviation, 1.2). The average assessment time was 1.9 hours (standard deviation, 0.7). The overall average reader sensitivity, specificity, and accuracy for detecting suspicious findings with histologic confirmation of cancer at the surgical margin for all eight readers were 80%, 87%, and 87%, respectively. Radiologists demonstrated the highest average among the disciplines, 85%, 93%, and 94%, followed by pathologists, 79%, 90%, and 84%, and surgeons, 76%, 84%, and 82% respectively. Conclusions With relatively short training (3.4 hours), readers from different medical specialties were able to distinguish suspicious from non-suspicious OCT imaging findings in ex vivo breast tissue as confirmed by histology. These results support the potential of OCT as a real-time intraoperative tool for post-lumpectomy specimen margin assessment.

The role of MRI in the workup of newly diagnosed breast cancer patients remains controversial. Breast MRI detects additional disease, but this has not translated into improved outcomes. In light of a dramatic rise in MRI use, we investigated patterns of MRI ordering for newly diagnosed breast cancer. All newly diagnosed breast cancer cases presenting for surgical management to a specialized breast center from 2011 to 2013 were reviewed. Patients who had an MRI ordered by their operating surgeon were compared with those who had an MRI completed previously. Of 1037 patients, 504 (49%) with newly diagnosed breast cancer underwent MRI as part of their pre-operative evaluation. Variables associated with MRI use included commercial insurance, increased breast density, genetic testing, mamographically occult disease, and lobular pathology. Of women who presented to our center with an MRI already completed, 63 per cent were ordered by a primary care provider. Of the 504 patients, 233 (44%) who had an MRI underwent an additional biopsy, and 166 (33%) had a resultant change in management. There was no significant difference in MRI-directed change in patient care depending on ordering provider. Further research is needed to develop evidence-based guidelines for preoperative MRI evaluation to optimize patient outcomes.

Controversy surrounds management of lobular neoplasia (LN), [atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS)], diagnosed on core needle biopsy (CNB). Retrospective series of pure ALH and LCIS reported “upgrade” rate to DCIS or invasive cancer in 0–40%. Few reports document radiologic/pathologic correlation to exclude cases of discordance that are the likely source of most upgrades, and there is minimal data on outcomes with follow-up imaging and clinical surveillance. Cases of LN alone on CNB (2001–2014) were reviewed. CNB yielding LN with other pathologic findings for which surgery was indicated were excluded. All patients had either surgical excision or clinical follow-up with breast imaging. All cases included were subject to radiologic–pathologic correlation after biopsy. 178 cases were identified out of 62213 (0.3%). 115 (65%) patients underwent surgery, and 54 (30%) patients had surveillance for > 12 months (mean = 55 months). Of the patients who underwent surgical excision, 13/115 (11%) were malignant. Eight of these 13 found malignancy at excision when CNB results were considered discordant (5 DCIS, and 3 invasive lobular carcinoma), with the remainder, 5/115 (4%), having a true pathologic upgrade: 3 DCIS, and 2 microinvasive lobular carcinoma. Among 54 patients not having excision, 12/54 (22%) underwent subsequent CNB with only 1 carcinoma found at the initial biopsy site. Surgical excision of LN yields a low upgrade rate when careful consideration is given to radiologic/pathologic correlation to exclude cases of discordance. Observation with interval breast imaging is a reasonable alternative for most cases.

TP53 is the most commonly mutated tumor suppressor gene and its mutation drives tumorigenesis. Using ChIP-seq for p53 in the absence of acute cell stress, we found that wild-type but not mutant p53 binds and activates numerous tumor suppressor genes, including PTEN, STK11(LKB1), miR-34a, KDM6A(UTX), FOXO1, PHLDA3, and TNFRSF10B through consensus binding sites in enhancers and promoters. Depletion of p53 reduced expression of these target genes, and analysis across 18 tumor types showed that mutation of TP53 associated with reduced expression of many of these genes. Regarding PTEN, p53 activated expression of a luciferase reporter gene containing the p53-consensus site in the PTEN enhancer, and homozygous deletion of this region in cells decreased PTEN expression and increased growth and transformation. These findings show that p53 maintains expression of a team of tumor suppressor genes that may together with the stress-induced targets mediate the ability of p53 to suppress cancer development. p53 mutations selected during tumor initiation and progression, thus, inactivate multiple tumor suppressor genes in parallel, which could account for the high frequency of p53 mutations in cancer. Implications: In this study, we investigate the activities of p53 under normal low-stress conditions and discover that p53 is capable of maintaining the expression of a group of important tumor suppressor genes at baseline, many of which are haploinsufficient, which could contribute to p53-mediated tumor suppression. Mol Cancer Res; 15(8); 1051–62. ©2017 AACR.

Background Nonpalpable breast lesions require localization before excision. This is most commonly performed with a wire (WL) or a radioactive seed (SL), which is placed into the breast under radiographic guidance. Although there are advantages of each modality, there are no guidelines to address which patients should undergo WL versus SL. We investigated factors influencing the selection of SL versus WL at our institution and assessed patient satisfaction with each procedure. Methods Patients undergoing preoperative localization of nonpalpable breast lesions from May 2014 through August 2015 were included. Physicians were surveyed on surgical scheduling to evaluate factors influencing the decision to perform SL or WL. Patient satisfaction was evaluated with a survey at the first postoperative visit. Retrospective chart review was performed. Results 341 patients were included: 104 (30%) patients underwent SL and 237 (70%) underwent WL. There was no difference in patient age, benign versus malignant disease, or need for concomitant axillary surgery comparing the SL versus WL groups. Physician survey indicated that 18% of patients were candidates for WL only. Of the patients who were eligible for both, 88 (41%) ultimately underwent SL and 126 (59%) had WL. The most commonly cited reason for selection of one localization method or the other was physician preference, followed by patient preference or avoiding additional visit. There was no significant difference in self-reported preoperative anxiety level, convenience of the localization procedure, pain of the localization procedure, operative experience, postoperative pain level or medication requirement, or overall patient satisfaction comparing patients who underwent SL and WL. Conclusions SL and WL offer patients similar comfort and satisfaction. Factors influencing selection of one modality over the other include both logistic and clinical considerations.

Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced HER2 + breast cancer (BC). Optimal sequencing of treatment (NAC vs. surgery first) is less clear cut in stage I (T1N0) HER2 + BC, where information from surgical pathology could impact adjuvant treatment decisions. Utilizing the NCDB, we evaluated the trend of NAC use compared to upfront surgery in patients with small HER2 + BC.We identified NCDB female patients diagnosed with T1 N0 HER2 + BC from 2010 through 2015. Prevalence ratios (PR) using multivariable robust Poisson regression models were calculated to measure the association between baseline characteristics and the receipt of NAC. Analysis of trends over time was denoted by annual percent change (APC) of NAC versus surgery upfront.Of the 14,949 that received chemotherapy and anti-HER2 therapy during the study period, overall 1281 (8.6%) received NAC and 13,668 (91.4%) received adjuvant treatment. Patients receiving NAC increased annually from 4.2% in 2010 to 17.3% in 2015, with the most rapid increase occurring between years 2013 (8.5%) and 2014 (14.2%). The greatest increase was seen in patients with cT1c tumors with an APC of 37.8% over the study period (95% CI 29.0, 47.3%, p 0.01), although a significant trend was likewise seen in patients with cT1a (APC = 26.1%,95% CI 1.59, 56.6%), and cT1b (APC = 27.4%, 95% CI 18.0, 37.7%) tumors. Predictors of neoadjuvant therapy receipt were age younger than 50 (PR = 1.69, 95% CI 1.52, 1.89), Mountain/Pacific area (PR = 1.24, 95% CI 1.05, 1.46), and estrogen receptor negativity (ER- PR + : PR = 2.01, 95% CI 1.51, 2.68; ER- PR- : PR = 1.49, 95% CI 1.32, 1.69).Neoadjuvant therapy for T1 N0 HER2 + BC increased over the study period and was mostly due increased use in clinical T1c tumors. This may be consistent with secular change in Pertuzumab treatment following FDA approval in 2013.

Pregnancy is associated with a transient increase in risk for breast cancer. However, the mechanism underlying pregnancy‐associated breast cancer (PABC) is poorly understood. Here, we identify the protease pappalysin‐1 (PAPP‐A) as a pregnancy‐dependent oncogene. Transgenic expression of PAPP‐A in the mouse mammary gland during pregnancy and involution promotes the deposition of collagen. We demonstrate that collagen facilitates the proteolysis of IGFBP‐4 and IGFBP‐5 by PAPP‐A, resulting in increased proliferative signaling during gestation and a delayed involution. However, while studying the effect of lactation, we found that although PAPP‐A transgenic mice lactating for an extended period of time do not develop mammary tumors, those that lactate for a short period develop mammary tumors characterized by a tumor‐associated collagen signature (TACS‐3). Mechanistically, we found that the protective effect of lactation is associated with the expression of inhibitors of PAPP‐A, STC1, and STC2. Collectively, these results identify PAPP‐A as a pregnancy‐dependent oncogene while also showing that extended lactation is protective against PAPP‐A‐mediated carcinogenesis. Our results offer the first mechanism that explains the link between breast cancer, pregnancy, and breastfeeding.

The role of MRI in the workup of newly diagnosed breast cancer patients remains controversial. Breast MRI detects additional disease, but this has not translated into improved outcomes. In light of a dramatic rise in MRI use, we investigated patterns of MRI ordering for newly diagnosed breast cancer. All newly diagnosed breast cancer cases presenting for surgical management to a specialized breast center from 2011 to 2013 were reviewed. Patients who had an MRI ordered by their operating surgeon were compared with those who had an MRI completed previously. Of 1037 patients, 504 (49%) with newly diagnosed breast cancer underwent MRI as part of their preoperative evaluation. Variables associated with MRI use included commercial insurance, increased breast density, genetic testing, mamographically occult disease, and lobular pathology. Of women who presented to our center with an MRI already completed, 63 per cent were ordered by a primary care provider. Of the 504 patients, 233 (44%) who had an MRI underwent an additional biopsy, and 166 (33%) had a resultant change in management. There was no significant difference in MRI-directed change in patient care depending on ordering provider. Further research is needed to develop evidence-based guidelines for preoperative MRI evaluation to optimize patient outcomes.

Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R-induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER-independent PIK3CA-mutant breast cancer.

At times we encounter clinical prob-lems for which there are no directlyapplicable evidence-based solutions,but we are compelled by circumstan-ces to act. When doing so we rely onrelated evidence, general principles ofbest medical practice, and our expe-rience. Each “Current Clinical Prac-tice” feature article in Seminars inOncology describes such a challeng-ing presentation and offers treatmentapproaches from selected specialists.We invite readers' comments andquestions, which, with your approval,will be published in subsequentissues of the Journal. It is hoped thatsharing our views and experienceswill better inform our managementdecisions when we next encountersimilar challenging patients. Pleasesend your comments on the articles,your challenging cases, and yourtreatment successes to me at dr.gjmorris@gmail.com. I look forward to alively discussion.Gloria J. Morris, MD, PhDCurrent Clinical Practice FeatureEditor

Purpose: Despite the fact that interstitial fluid (IF) represents a third of our body fluid, it is the most poorly understood body fluid in medicine. Increased IF pressure is thought to result from the increased deposition of extracellular matrix in the affected tissue preventing its reabsorption. In the cancer field, increased rigidity surrounding a cancerous mass remains the main reason that palpation and radiologic examination, such as mammography, are used for cancer detection. While the pressure produced by IF has been considered, the biochemical composition of IF has not been considered in its effect on tumors. Experimental Design: We classified 135 IF samples from bilateral mastectomy patients based on their ability to promote the invasion of breast cancer cells. Results: We observed a wide range of invasion scores. Patients with high-grade primary tumors at diagnosis had higher IF invasion scores. In mice, injections of high-score IF (IFHigh) in a normal mammary gland promotes ductal hyperplasia, increased collagen deposition, and local invasion. In a mouse model of residual disease, IFHigh increased disease progression and promoted aggressive visceral metastases. Mechanistically, we found that IFHigh induces myofibroblast differentiation and collagen production through activation of CLIC4. IFHigh also downregulates RYBP, leading to degradation of p53. Furthermore, in mammary glands of heterozygous p53-mutant knock-in mice, IFHigh promotes spontaneous tumor formation. Conclusions: Our study indicates that IF can increase the deposition of extracellular matrix and raises the provocative possibility that they play an active role in the predisposition, development, and clinical course of sporadic breast cancers. Clin Cancer Res; 23(18); 5446–59. ©2017 AACR.

This study aimed to assess whether different breast cancer subspecialty physicians can be trained to distinguish non-suspicious from suspicious areas of post-lumpectomy specimen margin in patients with breast cancer using optical coherence tomography (OCT) images (a near-infrared based imaging technique) with final histology as the reference standard.This institutional review board-exempt, Health Insurance Portability and Accountability Act-compliant study was performed on 63 surgically excised breast specimens from 35 female patients, creating a 90-case atlas containing both non-suspicious and suspicious areas for cancer. OCT images of the specimens were performed, providing 6.5-15 µm resolution with tissue visualization 1-2 mm subsurface. From the 90-case atlas, 40 cases were chosen for training and 40 were randomly selected for reader assessment. Three breast imaging radiologists, two pathologists, two breast surgeons, and one non-clinical reader were trained and assessed for ability to distinguish non-suspicious from suspicious findings blinded to clinical data and corresponding histology slides. Duration of training and assessment, sensitivity, specificity, positive predictive value, negative predictive value, and the area under the curve for each reader were calculated as well as averages by subspecialty.The average training time was 3.4 hours (standard deviation, 1.2). The average assessment time was 1.9 hours (standard deviation, 0.7). The overall average reader sensitivity, specificity, and accuracy for detecting suspicious findings with histologic confirmation of cancer at the surgical margin for all eight readers were 80%, 87%, and 87%, respectively. Radiologists demonstrated the highest average among the disciplines, 85%, 93%, and 94%, followed by pathologists, 79%, 90%, and 84%, and surgeons, 76%, 84%, and 82% respectively.With relatively short training (3.4 hours), readers from different medical specialties were able to distinguish suspicious from non-suspicious OCT imaging findings in ex vivo breast tissue as confirmed by histology. These results support the potential of OCT as a real-time intraoperative tool for post-lumpectomy specimen margin assessment.

Purpose To determine the utility and rate of biopsy in women with a positive history of breast cancer screened with MRI. Methods Retrospective review of 491 breast MRI screening examinations in women with a personal history of breast cancer. Results In total, 107 biopsies were performed, an average of 0.09 biopsies per person year. The positive predictive value for biopsies prompted by MRI findings was 0.24 (95% C.I. 0.10–0.38). Eight of the nine subsequent cancers were initially identified on screening MRI alone. Conclusion Surveillance MRI in breast cancer survivors may increase detection of subsequent cancers while increasing rate of biopsy.

The proportion of patients eligible for breast-conservation therapy (BCT) yet opting for mastectomy is increasing. This decision is often driven by the desire to eliminate future screening and/or biopsy of the remaining breast or breasts. This study investigated the incidence of post-mastectomy imaging and biopsy. A retrospective review of all unilateral mastectomy (UM) and bilateral mastectomy (BM) cases managed at a single institution was undertaken. Post-mastectomy imaging and biopsy rates were determined. Between 2009 and 2015, 185 UM and 200 BM cases managed for breast cancer were identified. The mean follow-up period was 30 months (range 3–75 months). For the patients with UM, imaging studies and biopsies done on the contralateral side were excluded given the standard of care for continued surveillance of the contralateral breast. Of the 185 UM patients, 19 (10%) underwent ipsilateral imaging (all ultrasounds) for physical examination findings, 11 (6%) underwent biopsy, and 2 (1%) had malignant findings. Of the 200 BM patients, 31 (15.5%) required imaging (29 ultrasounds and 2 MRIs), with 76% of the ultrasounds performed on the side with previous cancer. Subsequently, 16 (8%) of the BM patients had biopsy, with 11 (69%) of the 16 biopsies performed on the ipsilateral side. Three (1.5%) of the biopsies done on ipsilateral side demonstrated malignancy, whereas all the contralateral biopsies were benign. For 10–15.5% of patients who undergo mastectomy, either UM or BM, subsequent imaging is required, whereas 6–8% undergo biopsy. The yield of malignancy is low, approximately 1%. Thus, after mastectomy, the need for imaging and biopsy is not eliminated. This information is critical for patient understanding and expectation related to surgical decision making.

The purposes of this article are to describe two cases of breast cancer in male-to-female transsexuals and to review eight cases previously reported in the literature.Breast cancer occurs in male-to-female transsexuals who receive high doses of exogenous estrogen and develop breast tissue histologically identical to that of a biologically female breast. This exposure to estrogen results in increased risk of breast cancer. The first patient described is a male-to-female transsexual with screening-detected ductal carcinoma in situ and a family history of breast cancer. The other patient is a male-to-female transsexual with invasive ductal carcinoma that was occult on diagnostic digital mammographic and ultrasound findings but visualized on digital breast tomosynthesis and breast MR images. The analysis of the eight previously reported cases showed that breast cancer in male-to-female transsexuals occurs at a younger age and is more frequently estrogen receptor negative than breast cancer in others born biologically male. Screening for breast cancer in male-to-female transsexuals should be undertaken for those with additional risk factors (e.g., family history, BRCA2 mutation, Klinefelter syndrome) and should be available to those who desire screening, preferably in a clinical trial.

Background. Breast pathology is a challenging field, and previous work has shown discrepancies in diagnoses, even among experts. We set out to determine whether mandatory pathology review changes the diagnosis or surgical management of breast disease. Methods. Cases were referred for pathology review after patients presented for surgical opinion to the Dubin Breast Center at Mount Sinai Medical Center over the course of 2 years. Surgical pathologists with expertise in breast disease reviewed slides submitted from the primary institution and rendered a second opinion diagnosis. Comparison of these reports was performed for evaluation of major changes in diagnosis and definitive surgical management. Results. A total of 306 patients with 430 biopsy specimens were reviewed. Change in diagnosis was documented in 72 (17 %) of 430 cases and change in surgical management in 41 (10 %). A change in diagnosis was more likely to occur in patients originally diagnosed with benign rather than malignant disease (31 vs. 7 %, p \ 0.001). Twelve (7 %) of 169 specimens initially diagnosed as benign were reclassified as malignant. A malignant diagnosis was changed to benign in 4 (2 %) of 261 cases. Change in diagnosis was less common in specimens originating from commercial laboratories than community hospitals or university hospitals (8, 19, 21 %, p = 0.023). Change in management was not dependent on initial institution. Type of biopsy specimen (surgical or core) did not influence diagnostic or management changes. Conclusions. We recommend considering breast pathology review based on the individual clinical scenario, regardless of initial pathologic diagnosis or originating institution.

Patient decision-making regarding breast cancer surgery is multifactorial, and patients derive information on surgical treatment options from a variety of sources which may have an impact on choice of surgery. We investigated the role of different information sources in patient decision-making regarding breast cancer surgery. Two hundred and sixty-eight patients with breast cancer, eligible for breast-conserving therapy were surveyed in the immediate preoperative period, and clinical data were also collected. This survey evaluated the scope and features of patient-driven research regarding their ultimate choice of surgical treatment. The two most common sources of information used by patients were written material from surgeons (199/268–74%) and the Internet (184/268–69%). There was a trend for women who chose bilateral mastectomy to use the Internet more frequently than those choosing unilateral mastectomy ( P = 0.056). Number of surgeons consulted, genetic testing, and MRI were significant predictors of patient choice of mastectomy over breast-conserving therapy. Multivariate analysis showed that the number of surgeons consulted ( P < 0.001) and genetic testing ( P < 0.001) were independent predictors of choosing mastectomy, whereas MRI was not. In conclusions, understanding factors driving patient decision-making may promote more effective education for patients requiring breast cancer surgery.

Current guidelines state that "no ink on tumor" constitutes adequate surgical margins for lumpectomy specimens. However, there remains uncertainty when tumor is close (1 mm) to multiple inked margins.All local excisions for invasive breast cancer during 3 years at one center were reviewed. Tumor characteristics, margin status, patient age, reoperations, and pathology of reexcised specimen were recorded. Chi-square analysis and regression models were used to identify factors associated with residual disease upon reoperation.In 533 lumpectomies for invasive cancer, 60 (11 %) had at least one positive margin, and 106 (20 %) had one or more close margin. Multiple margins were either close or positive in 67 cases. Reoperation was performed in 125 of 533 cases (23 %) for close or positive margins. Positive margins were significantly more likely to undergo reoperation compared with close margins (p 0.001). On reoperation, 73 of 125 (58 %) demonstrated residual cancer, including 39 of 68 (57 %) with close margins, and 34 of 57 (60 %) with positive margins (p = 0.52). When multiple margins were close or positive, residual cancer was found on reexcision in 45 of 59 (76 %) cases as opposed to 34 of 79 (43 %) cases with only one involved margin (p 0.001). When controlling for other factors, positive margins were no more associated with residual disease than close margins (p = 0.32), whereas multiple close or positive margins were associated with significantly higher risk of residual disease (odds ratio 6.1; p = 0.002; 95 % confidence interval 2.6-14.45).The only significant predictor of residual tumor was multiple close or positive margins. It may be appropriate to recommend reexcision for patients with multiple close margins.