Rates of high-risk screening prior to a breast cancer diagnosis in patients under age 40.

BACKGROUND: NCCN Guidelines recommend screening young women with an increased breast cancer risk (>20 â€‹% lifetime risk). We sought to evaluate our institutional rates of high-risk screening in young breast cancer patients prior to their diagnoses." METHODS: A single-institution retrospective review (2013-2018) was performed investigating risk scores (Tyrer-Cuzick model) and characteristics of breast cancer patients (age <40 â€‹y) prior to diagnosis. RESULTS: 92 breast cancer patients age <40 â€‹y were identified (average age 34.5). Only 3.3 â€‹% (n â€‹= â€‹3) underwent appropriate screening, despite 35.8 â€‹% meeting high-risk criteria. Nearly all patients underwent genetic testing (98.9 â€‹%) with pathogenic mutations identified in 36.5 â€‹%, including 15.3 â€‹% with BRCA1/2 mutations. CONCLUSIONS: This analysis highlights a significant discrepancy between those meeting criteria for high-risk screening and those who underwent appropriate screening. We identified that this cohort carries significant genetic burden. Future analysis should investigate these findings on a broader scale and strategies to improve screening.

The Impact of Frailty on Adjuvant Therapies Not Offered to or Declined by Breast Cancer Surgery Patients.

INTRODUCTION: The impact of frailty on adjuvant therapies not offered to or declined by elderly breast cancer surgery patients has been understudied. METHODS: This is a retrospective review of a prospectively managed single-center database including all breast cancer patients >65 years undergoing surgery in 2021. Frailty was determined using an electronic frailty index (eFI) derived from electronic health data. Patients were categorized as Fit (eFI ≤ .10), Pre-frail (.10 < eFI ≤.21), or Frail (eFI > .21). Chart review was performed to collect data on adjuvant therapies not offered or declined. Descriptive statistics and logistic regression were performed. RESULTS: Of 133 patients, 16.5% were frail, 46.6% were pre-frail, and 36.8% were fit. Demographics were similar among groups except age and comorbidities. Of those with adjuvant therapy indicated (n = 123), 15.4% were not offered at least one indicated therapy. Of those offered therapy, some therapy was declined in 22.7%. Frail patients more often were not offered or declined some therapy (frail: 63.2%, pre-frail 36.2%, fit: 28.2%, P = .03). Frailty was associated with having some therapy not offered or declined on univariate modeling (OR 4.4 95% CI 1.4-13.5, P = .01) but not on multivariate. Being frail was associated with higher odds of readmission at 6 months on multivariate analysis (OR 9.5, 95% CI: 1.7-54.2. P = .01). CONCLUSION: Over half of frail patients are not offered or decline some adjuvant therapy. The impact of this requires further study. Given their higher odds of readmission, frail patients require close postoperative monitoring to prevent the interruption of adjuvant therapies.

Does Preoperative MRI Reduce Positive Margins after Breast-Conserving Surgery?

BACKGROUND: Breast-conserving surgery (BCS) is a mainstay for breast cancer management, and obtaining negative margins is critical. Some have advocated for the use of preoperative magnetic resonance imaging (MRI) in reducing positive margins after BCS. We sought to determine whether preoperative MRI was associated with reduced positive margins. PATIENTS AND METHODS: The SHAVE/SHAVE2 trials were multicenter trials in ten US centers with patients with stage 0-3 breast cancer undergoing BCS. Use of preoperative MRI was at the discretion of the surgeon. We evaluated whether or not preoperative MRI was associated with margin status prior to randomization regarding resection of cavity with shave margins. RESULTS: A total of 631 patients participated. Median age was 64 (range 29-94) years, with a median tumor size of 1.3 cm (range 0.1-9.3 cm). Patient factors included 26.1% of patients (165) had palpable tumors, and 6.5% (41) received neoadjuvant chemotherapy. Tumor factors were notable for invasive lobular histology in 7.0% (44) and extensive intraductal component (EIC) in 32.8% (207). A preoperative MRI was performed in 193 (30.6%) patients. Those who underwent preoperative MRI were less likely to have a positive margin (31.1% versus 38.8%), although this difference was not statistically significant (p = 0.073). On multivariate analysis, controlling for patient and tumor factors, utilization of preoperative MRI was not a significant factor in predicting margin status (p = 0.110). Rather, age (p = 0.032) and tumor size (p = 0.040) were the only factors associated with margin status. CONCLUSION: These data suggest that preoperative MRI is not associated margin status; rather, patient age and tumor size are the associated factors.

Are Breast Cancer Patients Presenting With Higher Stage Since the COVID-19 Pandemic?

The impact of the COVID-19 pandemic on health care is vast and continuing to unfold. As much progress related to breast cancer has resulted from screening and public health measures, we analyzed the stage at which patients with breast cancer presented for surgical consultation from 2019 to 2021. From 2019 to 2021, retrospective analysis was performed on breast cancer patients, comparing differences in patient demographics and cancer stage at diagnosis pre- and post-recommendation (COVID-era) to postpone mammographic screening on March 26, 2020. Proportion analysis was performed to identify similar percentages for each stage, and a weighed stage severity score with sign test was crafted to compare overall stage for a given year. The study included 1107 breast cancer patients from breast cancer surgery registry. These groups were similar demographically. We performed analysis comparing pre-COVID and COVID-era stage severity score. This showed a statistically higher stage at presentation when comparing pre-COVID to COVID-era data (P = .0027). Additionally, we identified a higher rate of stage 3 at presentation or greater in the COVID-era with 7.79% pre-COVID vs 12.3% COVID-era (P = .016). We found that in comparing pre-COVID to COVID-era data that breast cancer patients presented with higher stages, in particular, stage 3 or higher stage disease. This analysis reveals the impact of COVID on the multidisciplinary treatment of breast cancer patients. Additional efforts are needed to address the stage migration, the disproportionate burden of disease, and the access to care.

Intestinal Microbiota Influence Doxorubicin Responsiveness in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is highly aggressive with a poor 5-year survival rate. Targeted therapy options are limited and most TNBC patients are treated with chemotherapy. This study aimed to determine whether doxorubicin (Dox) shifts the gut microbiome and whether gut microbiome populations influence chemotherapeutic responsiveness. Female BALB/c mice (n = 115) were injected with 4T1-luciferase cells (a murine syngeneic TNBC model) and treated with Dox and/or antibiotics, high-fat diet-derived fecal microbiota transplant (HFD-FMT), or exogenous lipopolysaccharide (LPS). Metagenomic sequencing was performed on fecal DNA samples. Mice that received Dox were stratified into Dox responders or Dox nonresponders. Mice from the Dox responders and antibiotics + Dox groups displayed reduced tumor weight and metastatic burden. Metagenomic analysis showed that Dox was associated with increased Akkermansia muciniphila proportional abundance. Moreover, Dox responders showed an elevated proportional abundance of Akkermansia muciniphila prior to Dox treatment. HFD-FMT potentiated tumor growth and decreased Dox responsiveness. Indeed, lipopolysaccharide, a structural component of Gram-negative bacteria, was increased in the plasma of Dox nonresponders and FMT + Dox mice. Treatment with exogenous LPS increases intestinal inflammation, reduces Dox responsiveness, and increases lung metastasis. Taken together, we show that modulating the gut microbiota through antibiotics, HFD-FMT, or by administering LPS influenced TNBC chemotherapy responsiveness, lung metastasis, and intestinal inflammation.

Omission of Radiation in Conservative Treatment for Breast Cancer: Opportunity for De-escalation of Care.

INTRODUCTION: De-escalation of breast cancer treatment aims to reduce patient and financial toxicity without compromising outcomes. Level I evidence and National Comprehensive Cancer Network guidelines support omission of adjuvant radiation in patients aged >70 y with hormone-sensitive, pT1N0M0 invasive breast cancer treated with endocrine therapy. We evaluated radiation use in patients eligible for guideline concordant omission of radiation. METHODS: Subgroup analysis of patients eligible for radiation omission from two pooled randomized controlled trials, which included stage 0-III breast cancer patients undergoing breast conserving surgery, was performed to evaluate factors associated with radiation use. RESULTS: Of 631 patients, 47 (7.4%) met radiation omission criteria and were treated by 14 surgeons at eight institutions. The mean age was 75.3 (standard deviation + 4.4) y. Majority of patients identified as White (n = 46; 97.9%) and non-Hispanic (n = 44; 93.6%). The mean tumor size was 1.0 cm; 37 patients (88.1%) had ductal, 4 patients (9.5%) had lobular, and 17 patients (40.5%) had low-grade disease. Among patients eligible for radiation omission, 34 (72.3%) patients received adjuvant radiation. Those who received radiation were significantly younger than those who did not (74 y, interquartile range = 4 y, versus 78 y, interquartile range = 11 y, P = 0.03). There was no difference in radiation use based on size (P = 0.4), histology (P = 0.5), grade (P = 0.7), race (P = 1), ethnicity (P = 0.6), institution (P = 0.1), gender of the surgeon (P = 0.7), or surgeon (P = 0.1). CONCLUSIONS: Fewer than 10% of patients undergoing breast conservation met criteria for radiation omission. Nearly three-quarters received radiation therapy with younger age being a driver of radiation use, suggesting ample opportunity for de-escalation, particularly among younger eligible patients.

Bilateral Diffuse Pseudoangiomatous Stromal Hyperplasia Necessitating Mastectomy.

Pseudoangiomatous stromal hyperplasia (PASH) is an uncommon, benign breast lesion often diagnosed incidentally and frequently mistaken for fibroadenoma given similar radiographic appearance. Histopathology classically reveals diffuse, dense fibrous stromal background with a complex network of spindle cells forming slit-like spaces, giving it the appearance of angiomatous proliferation. Surgical excision is generally not necessary. Here we present two unusual cases of PASH: an adolescent patient with bilateral rapid onset of symptoms, and a premenopausal patient with bilateral, diffuse, recurrent PASH. Both required mastectomy. We aim to highlight the variable nature of presentation and briefly review current management options.

Impact of the COVID-19 Pandemic on Breast Cancer Screening and Operative Treatment.

INTRODUCTION: The COVID-19 pandemic has impacted many areas of health care and had a significant impact on care delivery, including breast cancer. METHODS: To better understand the changes to detection and treatment of breast cancer at our institution, we analyzed mammogram rates (screening and diagnostic) and breast cancer operations in 2019-2020. Mammography rates were calculated using county level census data for eligible women (Z-test). For breast cancer staging, a stage severity score was analyzed with a Mann-Whitney U-test (two-tail, P < .05) with proportions derived from WFBH operative volume quarterly reports. Results: Data revealed a relative decline from 2019 to 2020 in breast cancer screening. Screening mammograms decreased by 44% or 1558 fewer screening mammograms (Z = 4.75, P < .00001) and by 21% or 771 fewer for diagnostic mammograms (Z = 2.16, P = .03). With regards to breast cancer operations, we did not identify a statistically significant difference in number of new breast cancer operations at WFBH with 340 cases in 2020 as compared to 384 cases in 2019 (P = .9905). We compared a breast cancer severity score (weighted by stage at time of operation), which did not reveal statistically significant difference in clinical stage of breast cancer at time of operation (P = .71, U = 28). CONCLUSION: Mammography was impacted more than breast surgery cases by the COVID-19 pandemic. More data needs to be collected to evaluate future morbidity and mortality related to breast cancer operations and persistent disparities related to delay in breast cancer care due to COVID-19.

Intraductal Papilloma on Breast Biopsy: Upstaging Rate and Implications for Practice Guidelines.

BACKGROUND: The recommendation for management of intraductal papilloma has not been clearly established and its surgical excision criteria remain controversial. This study determines the institutional malignancy upstage rate of benign intraductal papillomas and identifies risk factors for upstage. METHODS: Retrospective review was conducted on female patients who were diagnosed with intraductal papillomas without atypia on core needle biopsy at Atrium Health Wake Forest Baptist Hospital between 1/2012 and 6/2021. Patients were excluded if there was a concomitant malignancy or atypia or deemed to be discordant with imaging. Features associated with upstage on imaging and histopathology were obtained from the electronic medical record. RESULTS: This study included 245 intraductal papillomas without atypia in 231 women (mean age, 59.1 ± 12.3 [SD] years). Approximately 31% (76/245) of the papillomas were excised, whereas 69% (169/245) of the papillomas underwent surveillance. Of the patients who underwent excisional biopsy, upstage rate for DCIS was 1.3% (1/76) and 5.3% (4/76) for atypia. All of the papillomas upstaged to DCIS or atypia had lesion size ≥10 mm on imaging. Out of the 139 intraductal papillomas that underwent radiologic surveillance, two (1.4%) developed malignancy and three (2.2%) developed atypia. DISCUSSION: The risk of upstaging of intraductal papilloma without atypia to malignancy remains extremely low. Therefore, routine surgical excision may not be necessary. While the papillomas upstaged to either malignancy or atypia have size abnormality ≥10 mm, other potential selective excision criteria should be explored to further decrease the risk of an upstage.

Primary Breast Neuroendocrine Tumor.

Breast primary neuroendocrine tumors (BNETs) are rare, making up less than 1% of all breast carcinoma diagnosis. Their detection relies on physical exams and mammography. Diagnosis of primary BNET requires findings of no other source of neuroendocrine tumor (eg, pancreatic, lung, and appendix). Histopathologically, they typically stain positive for chromogranin A and/or synaptophysin, as do most neuroendocrine tumors. Currently, there are no agreed upon and standardized treatment protocols as it is a rare diagnosis. Treatment protocols are often built on anecdotal evidence and small case reports and series. Here we discuss a case of BNET in a 51-year-old female and discuss commonly encountered treatment protocols.

Upstage Rate of Complex Sclerosing Lesions/Radial Scars.

BACKGROUND: Radial scars (RS) and complex sclerosing lesions (CSL) are breast radiologic findings described as small, stellate lesions causing architectural distortion. This can mimic malignancy. Core needle biopsy (CNB) is often performed. Advances in breast imaging have led to increased detection of RS/CSL. The upstage rate of RS/CSL to in situ or invasive disease is 0-40%. We sought to determine the upstaging rate of RS/CSL to in situ, invasive disease, or high-risk lesion at our institution to create excision guidelines. METHODS: The pathology database of a single center was searched for RS/CSL, from January 2013 to September 2020. We included CNB without malignancy or high-risk lesion (eg, atypical ductal hyperplasia). Patient demographics, indications for biopsy, imaging findings, biopsy procedure, and final pathology were collected. RESULTS: Forty-four patients were included. 52.3% had CNB for architectural distortion on mammography, 18.2% for mass, 11.4% for calcifications, 2.3% for abnormal MRI, and 15.9% for multiple reasons (eg, calcifications and mass). Most had an ultrasound: 43.2% had no abnormality and 34.1% had a mass. All CNB were vacuum assisted, 65.9% with 9-gauge needle, and averaged 10.0 cores. 77.3% were stereotactic biopsies, 13.6% ultrasound, and 6.8% MRI. 59.1% had excision after CNB. 82.1% of patients did not upstage. One patient upstaged to invasive ductal carcinoma (3.6%) and two patients to high-risk lesion (7.1%). DISCUSSION: There was low upstage rate of RS/CSL on excisional biopsy. Centers could consider close surveillance for RS/CSL on CNB. Longer follow-up in cases of deferred excision is needed to ensure oncologic safety.

Are we choosing wisely? Drivers of preoperative MRI use in breast cancer patients.

INTRODUCTION: Factors contributing to the use of preoperative MRI remain poorly understood. METHODS: Data from a randomized controlled trial of stage 0-3 breast cancer patients undergoing breast conserving surgery between 2016 and 2018 were analyzed. RESULTS: Of the 396 patients in this trial, 32.6% had a preoperative MRI. Patient age, race, ethnicity, tumor histology, and use of neoadjuvant therapy were significant predictors of MRI use. On multivariate analysis, younger patients with invasive lobular tumors were more likely to have a preoperative MRI. Rates also varied significantly by individual surgeon (p < 0.001); in particular, female surgeons (39.9% vs. 24.0% for male surgeons, p = 0.001) and those in community practice (58.9% vs. 14.2% for academic, p < 0.001) were more likely to order preoperative MRI. Rates declined over the two years of the study, particularly among female surgeons. CONCLUSIONS: Preoperative MRI varies with patient age and tumor histology; however, there remains variability by individual surgeon.

Factors Affecting Time to Surgery in Breast Cancer Patients.

BACKGROUND: We sought to determine factors affecting time to surgery (TTS) to identify potential modifiable factors to improve timeliness of care. METHODS: Patients with clinical stage 0-3 breast cancer undergoing partial mastectomy in 2 clinical trials, conducted in ten centers across the US, were analyzed. No preoperative workup was mandated by the study; those receiving neoadjuvant therapy were excluded. RESULTS: The median TTS among the 583 patients in this cohort was 34 days (range: 1-289). Patient age, race, tumor palpability, and genomic subtype did not influence timeliness of care defined as TTS ≤30 days. Hispanic patients less likely to have a TTS ≤30 days (P = .001). There was significant variation in TTS by surgeon (P < .001); those practicing in an academic center more likely to have TTS ≤30 days than those in a community setting (55.1% vs 19.3%, P < .001). Patients who had a preoperative ultrasound had a similar TTS to those who did not (TTS ≤30 days 41.9% vs 51.9%, respectively, P = .109), but those who had a preoperative MRI had a significantly increased TTS (TTS ≤30 days 25.0% vs 50.9%, P < .001). On multivariate analysis, patient ethnicity was no longer significantly associated with TTS ≤30 (P = .150). Rather, use of MRI (OR: .438; 95% CI: .287-.668, P < .001) and community practice type (OR: .324; 95% CI: .194-.541, P < .001) remained independent predictors of lower likelihood of TTS ≤30 days. CONCLUSIONS: Preoperative MRI significantly increases time to surgery; surgeons should consider this in deciding on its use.

Evaluation of the Axillary Surgery Performed in Clinically Node-Positive Breast Cancer Patients Following Neoadjuvant Chemotherapy.

BACKGROUND: The American College of Surgeons Oncology Group Z1071 trial in 2013 demonstrated the fesability of sentinel lymph node biopsy in clinically node-positive patients following neoadjuvant chemotherapy. The goal of this study was to determine the continued impact of this study on our practice pattern. MATERIALS AND METHODS: This is a retrospective review of institutional changes in the management of axillary nodal disease following the publication of Z1071. Patients with clinically node-positive disease that completed neoadjuvant chemotherapy between 2014 and 2020 were included. The Cocoran-Armitage trend test was used to analyze change in categorical variables over time, and the Spearman's rank coefficient was used to analyze two-ranked variables. RESULTS: A cohort of 102 patients were included in the study and demonstrated that the number of sentinel lymph node biopsies to evaluate axillary disease increased over time. Additionally, the number of biopsies of suspicious nodes, and the use of marker clips on the biopsied nodes increased over time. CONCLUSION: Our institution has continued to incorporate the result from Z1071 in our practice patterns.

Does Localization Technique Matter for Non-palpable Breast Cancers?

BACKGROUND: There are several techniques for localization of non-palpable breast tumors, but comparisons of these techniques in terms of margin positivity and volume of tissue resected are lacking. METHODS: Between 2011-2013 and 2016-2018, 2 randomized controlled trials involving 10 centers across the United States accrued 631 patients with stage 0-3 breast cancer, all of whom underwent breast conserving surgery. Of these, 522 had residual non-palpable tumors for which localization was required. The localization technique was left to the discretion of the individual surgeon. We compared margin positivity and volume of tissue resected between various localization techniques. RESULTS: The majority of the patients (n = 465; 89.1%) had wire localization (WL), 50 (9.6%) had radioactive seed (RS) localization, and 7 (1.3%) had Savi Scout (SS) localization. On bivariate analysis, there was no difference in terms of margin positivity (37.8% vs. 28.0% vs. 28.6%, P = .339) nor re-excision rates (13.3% vs. 12.0% vs. 14.3%, P = .961) for the WL, RS, and SS groups, respectively. Further, the volume of tissue removed was not significantly different between the 3 groups (71.9 cm3 vs. 55.8 cm3 vs. 86.6 cm3 for the WL, RS, and SS groups, respectively, P = .340). On multivariate analysis, margin status was affected by tumor size (OR = 1.336; 95% CI: 1.148-1.554, P<.001) but not by type of localization (P = .670). CONCLUSIONS: While there are a number of methods for tumor localization, choice of technique does not seem to influence volume of tissue resected nor margin status.

Bulk and Single-Cell Profiling of Breast Tumors Identifies TREM-1 as a Dominant Immune Suppressive Marker Associated With Poor Outcomes.

BACKGROUND: Triggering receptor expressed on myeloid cells (TREM)-1 is a key mediator of innate immunity previously associated with the severity of inflammatory disorders, and more recently, the inferior survival of lung and liver cancer patients. Here, we investigated the prognostic impact and immunological correlates of TREM1 expression in breast tumors. METHODS: Breast tumor microarray and RNAseq expression profiles (n=4,364 tumors) were analyzed for associations between gene expression, tumor immune subtypes, distant metastasis-free survival (DMFS) and clinical response to neoadjuvant chemotherapy (NAC). Single-cell (sc)RNAseq was performed using the 10X Genomics platform. Statistical associations were assessed by logistic regression, Cox regression, Kaplan-Meier analysis, Spearman correlation, Student's t-test and Chi-square test. RESULTS: In pre-treatment biopsies, TREM1 and known TREM-1 inducible cytokines (IL1B, IL8) were discovered by a statistical ranking procedure as top genes for which high expression was associated with reduced response to NAC, but only in the context of immunologically "hot" tumors otherwise associated with a high NAC response rate. In surgical specimens, TREM1 expression varied among tumor molecular subtypes, with highest expression in the more aggressive subtypes (Basal-like, HER2-E). High TREM1 significantly and reproducibly associated with inferior distant metastasis-free survival (DMFS), independent of conventional prognostic markers. Notably, the association between high TREM1 and inferior DMFS was most prominent in the subset of immunogenic tumors that exhibited the immunologically hot phenotype and otherwise associated with superior DMFS. Further observations from bulk and single-cell RNAseq analyses indicated that TREM1 expression was significantly enriched in polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and M2-like macrophages, and correlated with downstream transcriptional targets of TREM-1 (IL8, IL-1B, IL6, MCP-1, SPP1, IL1RN, INHBA) which have been previously associated with pro-tumorigenic and immunosuppressive functions. CONCLUSIONS: Together, these findings indicate that increased TREM1 expression is prognostic of inferior breast cancer outcomes and may contribute to myeloid-mediated breast cancer progression and immune suppression.

Resection of Cavity Shave Margins in Stage 0-III Breast Cancer Patients Undergoing Breast Conserving Surgery: A Prospective Multicenter Randomized Controlled Trial.

OBJECTIVE: Single-center studies have demonstrated that resection of cavity shave margins (CSM) halves the rate of positive margins and re-excision in breast cancer patients undergoing partial mastectomy (PM). We sought to determine if these findings were externally generalizable across practice settings. METHODS: In this multicenter randomized controlled trial occurring in 9 centers across the United States, stage 0-III breast cancer patients undergoing PM were randomly assigned to either have resection of CSM ("shave" group) or not ("no shave" group). Randomization occurred intraoperatively, after the surgeon had completed their standard PM. Primary outcome measures were positive margin and re-excision rates. RESULTS: Between July 28, 2016 and April 13, 2018, 400 patients were enrolled in this trial. Four patients (2 in each arm) did not meet inclusion criteria after randomization, leaving 396 patients for analysis: 196 in the "shave" group and 200 to the "no shave" group. Median patient age was 65 years (range; 29-94). Groups were well matched at baseline for demographic and clinicopathologic factors. Prior to randomization, positive margin rates were similar in the "shave" and "no shave" groups (76/196 (38.8%) vs. 72/200 (36.0%), respectively, P = 0.604). After randomization, those in the "shave" group were significantly less likely than those in the "no shave" group to have positive margins (19/196 (9.7%) vs. 72/200 (36.0%), P < 0.001), and to require re-excision or mastectomy for margin clearance (17/196 (8.7%) vs. 47/200 (23.5%), P < 0.001). CONCLUSION: Resection of CSM significantly reduces positive margin and re-excision rates in patients undergoing PM.