Organizational Breast Cancer Data Mart: A Solution for Assessing Outcomes of Imaging and Treatment.

PURPOSE: In the United States, a comprehensive national breast cancer registry (CR) does not exist. Thus, care and coverage decisions are based on data from population subsets, other countries, or models. We report a prototype real-world research data mart to assess mortality, morbidity, and costs for breast cancer diagnosis and treatment. METHODS: With institutional review board approval and Health Insurance Portability and Accountability Act (HIPPA) compliance, a multidisciplinary clinical and research data warehouse (RDW) expert group curated demographic, risk, imaging, pathology, treatment, and outcome data from the electronic health records (EHR), radiology (RIS), and CR for patients having breast imaging and/or a diagnosis of breast cancer in our institution from January 1, 2004, to December 31, 2020. Domains were defined by prebuilt views to extract data denormalized according to requirements from the existing RDW using an export, transform, load pattern. Data dictionaries were included. Structured query language was used for data cleaning. RESULTS: Five-hundred eighty-nine elements (EHR 311, RIS 211, and CR 67) were mapped to 27 domains; all, except one containing CR elements, had cancer and noncancer cohort views, resulting in a total of 53 views (average 12 elements/view; range, 4-67). EHR and RIS queries returned 497,218 patients with 2,967,364 imaging examinations and associated visit details. Cancer biology, treatment, and outcome details for 15,619 breast cancer cases were imported from the CR of our primary breast care facility for this prototype mart. CONCLUSION: Institutional real-world data marts enable comprehensive understanding of care outcomes within an organization. As clinical data sources become increasingly structured, such marts may be an important source for future interinstitution analysis and potentially an opportunity to create robust real-world results that could be used to support evidence-based national policy and care decisions for breast cancer.

Upgrade Rates of Variant Lobular Carcinoma In Situ Compared to Classic Lobular Carcinoma In Situ Diagnosed in Core Needle Biopsies: A 10-Year Single Institution Retrospective Study.

The primary aim of this study was to determine the upgrade rates of variant lobular carcinoma in situ (V-LCIS, ie, combined florid [F-LCIS] and pleomorphic [P-LCIS]) compared with classic LCIS (C-LCIS) when diagnosed on core needle biopsy (CNB). The secondary goal was to determine the rate of progression/development of invasive carcinoma on long-term follow-up after primary excision. After institutional review board approval, our institutional pathology database was searched for patients with "pure" LCIS diagnosed on CNB who underwent subsequent excision. Radiologic findings were reviewed, radiologic-pathologic (rad-path) correlation was performed, and follow-up patient outcome data were obtained. One hundred twenty cases of LCIS were identified on CNB (C-LCIS = 97, F-LCIS = 18, and P-LCIS = 5). Overall upgrade rates after excision for C-LCIS, F-LCIS, and P-LCIS were 14% (14/97), 44% (8/18), and 40% (2/5), respectively. Of the total cases, 79 (66%) were deemed rad-path concordant. Of these, the upgrade rate after excision for C-LCIS, F-LCIS, and P-LCIS was 7.5% (5 of 66), 40% (4 of 10), and 0% (0 of 3), respectively. The overall upgrade rate for V-LCIS was higher than for C-LCIS (P = .004), even for the cases deemed rad-path concordant (P value: .036). Most upgraded cases (23 of 24) showed pT1a disease or lower. With an average follow-up of 83 months, invasive carcinoma in the ipsilateral breast was identified in 8/120 (7%) cases. Six patients had died: 2 of (contralateral) breast cancer and 4 of other causes. Because of a high upgrade rate, V-LCIS diagnosed on CNB should always be excised. The upgrade rate for C-LCIS (even when rad-path concordant) is higher than reported in many other studies. Rad-path concordance read, surgical consultation, and individualized decision making are recommended for C-LCIS cases. The risk of developing invasive carcinoma after LCIS diagnosis is small (7% with ∼7-year follow-up), but active surveillance is required to diagnose early-stage disease.

Use of natural language understanding to facilitate surgical de-escalation of axillary staging in patients with breast cancer.

Natural language understanding (NLU) may be particularly well-equipped for enhanced data capture from the electronic health record (EHR) given its examination of both content- and context-driven extraction. We developed and applied a NLU model to examine rates of pathological node positivity (pN+) and rates of lymphedema to determine if omission of routine axillary staging could be extended to younger patients with ER+/cN0 disease. We found that rates of pN+ and arm lymphedema were similar between patients 55-69yo and ≥70yo, with rates of lymphedema exceeding rates of pN+ for clinical stage T1c and smaller disease. Data from our NLU model suggest that omission of SLNB might be extended beyond Choosing Wisely recommendations, limited to those over 70 years old, to all postmenopausal women with early-stage ER+/cN0 disease. These data support the recently-reported SOUND trial results and provide additional granularity to facilitate surgical de-escalation.

WCRC-25: A novel luminal Invasive Lobular Carcinoma cell line model.

Breast cancer is categorized by the molecular and histologic presentation of the tumor, with the major histologic subtypes being No Special Type (NST) and Invasive Lobular Carcinoma (ILC). ILC are characterized by growth in a single file discohesive manner with stromal infiltration attributed to their hallmark pathognomonic loss of E-cadherin ( CDH1 ). Few ILC cell line models are available to researchers. Here we report the successful establishment and characterization of a novel ILC cell line, WCRC-25, from a metastatic pleural effusion from a postmenopausal Caucasian woman with metastatic ILC. WCRC-25 is an ER-negative luminal epithelial ILC cell line with both luminal and Her2-like features. It exhibits anchorage independent growth and haptotactic migration towards Collagen I. Sequencing revealed a CDH1 Q706* truncating mutation, together with mutations in FOXA1, CTCF, BRCA2 and TP53 , which were also seen in a series of metastatic lesions from the patient. Copy number analyses revealed amplification and deletion of genes frequently altered in ILC while optical genome mapping revealed novel structural rearrangements. RNA-seq analysis comparing the primary tumor, metastases and the cell line revealed signatures for cell cycle progression and receptor tyrosine kinase signaling. To assess targetability, we treated WCRC-25 with AZD5363 and Alpelisib confirming WCRC-25 as susceptible to PI3K/AKT signaling inhibition as predicted by our RNA sequencing analysis. In conclusion, we report WCRC-25 as a novel ILC cell line with promise as a valuable research tool to advance our understanding of ILC and its therapeutic vulnerabilities. Financial support: The work was in part supported by a Susan G Komen Leadership Grant to SO (SAC160073) and NCI R01 CA252378 (SO/AVL). AVL and SO are Komen Scholars, Hillman Foundation Fellows and supported by BCRF. This project used the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource which is supported in part by award P30CA047904. This research was also supported in part by the University of Pittsburgh Center for Research Computing, RRID:SCR_022735, through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483. Finally, partial support was provided by the Magee-Womens Research Institute and Foundation, The Shear Family Foundation, and The Metastatic Breast Cancer Network.

Immune landscape in invasive ductal and lobular breast cancer reveals a divergent macrophage-driven microenvironment.

T cell-centric immunotherapies have shown modest clinical benefit thus far for estrogen receptor-positive (ER+) breast cancer. Despite accounting for 70% of all breast cancers, relatively little is known about the immunobiology of ER+ breast cancer in women with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). To investigate this, we performed phenotypic, transcriptional and functional analyses for a cohort of treatment-naive IDC (n = 94) and ILC (n = 87) tumors. We show that macrophages, and not T cells, are the predominant immune cells infiltrating the tumor bed and the most transcriptionally diverse cell subset between IDC and ILC. Analysis of cellular neighborhoods revealed an interplay between macrophages and T cells associated with longer disease-free survival in IDC but not ILC. Our datasets provide a rich resource for further interrogation into immune cell dynamics in ER+ IDC and ILC and highlight macrophages as a potential target for ER+ breast cancer.

Single-institution outcomes after excision of benign phyllodes tumors: low recurrence risk even with positive margins.

PURPOSE: Benign phyllodes tumors (BPT) are rare breast neoplasms with clinical behavior that poses low recurrence risk. Guidelines regarding appropriate margins recommend surgical excision to negative margins, sometimes requiring re-excision surgery. Contemporary experience suggests that re-excision in the face of positive margins may not be needed. METHODS: This is a retrospective review of a single-institution experience with BPT from 2010 to 2019 with 102 patients. Demographics, outcomes and follow-up were analyzed. RESULTS: The median age was 37 years. 95% had a pre-operative biopsy and only 6% were confirmed BPT before surgery.56% had positive margins and were more likely to be younger and have a pre-operative diagnosis of fibroadenoma. The median follow-up was 33 months. Between the positive and negative margin groups, recurrence rates were not significantly different (p = 0.87). CONCLUSION: Positive margins on excision of BPT poses a low recurrence risk and re-excision surgery is not necessary.

Surgical Nipple Delay and its Expanded Indications for Nipple-sparing Mastectomy.

Necrosis of the nipple-areolar complex (NAC) or surrounding skin has been reported in 6%-30% of nipple-sparing mastectomy (NSM) patients, with higher rates associated with larger breasts, previous breast surgery, previous radiation, and active smoking. The nipple delay (ND) procedure is known to improve viability of the NAC in NSM patients with high-risk factors. Methods: A single-institution retrospective review was done of patients who underwent ND and NSM or NSM alone from 2012 to 2022. Patient demographics, risk factors, and outcomes were compared. Results: Forty-two breasts received ND-NSM and 302 breasts received NSM alone. The ND-NSM group had significantly more high-risk factors, including elevated BMI (26.3 versus 22.9; P < 0.001), elevated prior breast surgery (50% versus 25%; P < 0.001), and greater mastectomy specimen weight (646.6 versus 303.2 g; P < 0.001). ND-NSM was more likely to have undergone preparatory mammoplasty before NSM (27% versus 1%; P < 0.001). There was no delay in NSM treatment from decision to pursue NSM (P = 0.483) or difference in skin necrosis (P = 0.256), NAC necrosis (P = 0.510), hematoma (P = 0.094), seroma (P = 0.137), or infection (P = 0.437) between groups. ND-NSM and NSM patients differed in total NAC necrosis (0% versus 3%) and implant loss (0% vs 13%), but not significantly. Conclusions: We demonstrated no NAC necrosis and no significant delay of treatment in higher risk ND-NSM patients. ND may allow higher risk patients to undergo NSM with similar morbidity as lower risk patients.

Mixed invasive ductal lobular carcinoma is clinically and pathologically more similar to invasive lobular than ductal carcinoma.

BACKGROUND: Mixed invasive ductal lobular carcinoma (mDLC) remains a poorly understood subtype of breast cancer composed of coexisting ductal and lobular components. METHODS: We sought to describe clinicopathologic characteristics and determine whether mDLC is clinically more similar to invasive ductal carcinoma (IDC) or invasive lobular carcinoma (ILC), using data from patients seen at the University of Pittsburgh Medical Center. RESULTS: We observed a higher concordance in clinicopathologic characteristics between mDLC and ILC, compared to IDC. There is a trend for higher rates of successful breast-conserving surgery after neoadjuvant chemotherapy in patients with mDLC compared to patients with ILC, in which it is known to be lower than in those with IDC. Metastatic patterns of mDLC demonstrate a propensity to develop in sites characteristic of both IDC and ILC. A meta-analysis evaluating mDLC showed shared features with both ILC and IDC with significantly more ER-positive and fewer high grades in mDLC compared to IDC, although mDLCs were significantly smaller and included fewer late-stage tumours compared to ILC. CONCLUSIONS: These findings support clinicopathologic characteristics of mDLC driven by individual ductal vs lobular components and given the dominance of lobular pathology, mDLC features are often more similar to ILC than IDC. This study exemplifies the complexity of mixed disease.

Postdischarge Nausea and Vomiting and Co-occurring Symptoms in Women Following Breast Cancer Surgery.

PURPOSE: The purpose of this study was to investigate the influence of potential co-occurring symptoms, including fatigue, sleep disturbance, anxiety, depressive symptoms, and pain, on the incidence of postdischarge nausea (PDN) measured two days following discharge to home after surgery for breast cancer. DESIGN: This study used a prospective, cross-sectional, observational design. METHODS: The sample was 334 women aged 27 to 88 years of age. Demographic data were collected from the patient and the medical record before surgery. Symptom data were collected 48 hours following surgery using the Patient Reported Outcome Measurement System (PROMIS) and numerical nausea and pain scales. FINDINGS: Eighty-five (25.4%) of study participants reported some nausea two days after discharge. Study participants who experienced PDN frequently described that it occurred after they left the hospital to drive home following their surgery. Unadjusted odds ratios showed the presence of co-occurring symptoms of anxiety, fatigue, sleep disturbance, and pain were all significantly associated with the presence of nausea 48 hours following surgery. Other significant factors associated with (PDN) were history of motion sickness, history of pregnancy-induced nausea, use of opioids, and type of surgery. CONCLUSIONS: Same-day surgery nurses providing postoperative education for women following surgery for breast cancer should explain to patients that nausea may occur after they are discharged, especially those with known motion sickness. In addition, patients should be informed that other symptoms, especially fatigue, sleep disturbance, and anxiety, may co-occur.

Dosimetry and Toxicity Outcomes in Patients Treated with Hypofractionated Regional Nodal Irradiation for Breast Cancer: What is the Best Dose-Volume Limit to Minimize Risks of Radiation Pneumonitis?

PURPOSE: Although published data have supported the use of hypofractionated regional nodal irradiation (HF-RNI) for breast cancer, limited dosimetric data exist to evaluate predictors of lung toxicity. The ongoing RT CHARM trial limits the percentage of ipsilateral lung volume that receives ≥18 Gy to 35 to 40%. We assessed dosimetry, toxicity, and disease outcomes in patients with breast cancer treated with HF-RNI with a particular focus on pneumonitis. METHODS AND MATERIALS: We retrospectively reviewed all patients with breast cancer treated with HF-RNI (40-43 Gy in 15-16 fractions) after either lumpectomy or mastectomy at The University of Pittsburgh Medical Center from September 2018 to December 2021 to collect dosimetric and outcomes data. All post-radiation therapy chest computed tomography (CT) scans were manually reviewed for evidence of acute (≤6 months postradiation) or chronic (>6 months postradiation) pneumonitis. RESULTS: One-hundred-ninety-one patients qualified with a median follow-up of 20.3 months (range, 5.1-42.2). Acute grade 1 (G1) pneumonitis was observed in 6.8% of the overall cohort (13 of 191 patients) and 39.4% of the patients (13 of 33) who received a chest CT ≤6 months postradiation therapy. Only 1 patient developed acute G2 pneumonitis. Chronic G1 pneumonitis was observed in 29.8% of the overall cohort (57 of 191 patients) and 77% of patients (57 of 74 patients) who received a chest CT >6 months postradiation therapy. No patients developed acute G3+ or chronic G2+ pneumonitis. CONCLUSIONS: Rates of symptomatic pneumonitis were low in this cohort of patients treated with HF-RNI, even with integration of HER2/neu-directed therapy, chemotherapy, hormone therapy, and internal mammary nodal irradiation. Lung V20Gy <26% appeared safe in this cohort to limit symptomatic pneumonitis, though this is not meant to represent the safe upper limit. Given the low event rate of symptomatic pneumonitis, data from larger cohorts will be needed to assess dosimetric predictors and the safe upper limit of lung dose.

Molecular classification and biomarkers of clinical outcome in breast ductal carcinoma in situ: Analysis of TBCRC 038 and RAHBT cohorts.

Ductal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We perform multiscale, integrated molecular profiling of DCIS with clinical outcomes by analyzing 774 DCIS samples from 542 patients with 7.3 years median follow-up from the Translational Breast Cancer Research Consortium 038 study and the Resource of Archival Breast Tissue cohorts. We identify 812 genes associated with ipsilateral recurrence within 5 years from treatment and develop a classifier that predicts DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions are identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.

Improving well-being for individuals with persistent pain after surgery for breast cancer, lobular carcinoma in situ, or ductal carcinoma in situ: A randomized clinical trial.

>276,000 Americans will be diagnosed with invasive breast cancer, lobular carcinoma in situ, or ductal carcinoma in situ this year and most will undergo breast surgery as part of their care. Although prognosis is excellent, many patients experience persistent post-surgical pain (PSP), which has no satisfactory pharmacological treatment. The causal contributions of pain-associated psychological factors (e.g., catastrophic thoughts about pain, psychological flexibility, self-efficacy) to the continuing burden of PSP have not yet been determined and may be opportune intervention targets. The randomized trial described here will compare the benefits of three manualized behavioral interventions for individuals with PSP. Participants will receive either: 1) self-guided health education (SGHE); 2) interventionist-guided health education (IGHE); or 3) interventionist-guided pain coping skills training with elements of acceptance and commitment therapy that specially target catastrophic thoughts about pain, self-efficacy, and psychological flexibility (CST-PSP). Participants will prospectively complete validated assessments of primary outcomes (PSP severity and interference) at baseline (pre-intervention) and 3-, 6-, and 12-months later. Validated measures of emotional distress and cancer-specific distress will be assessed as secondary outcomes. To test their roles as drivers of PSP, catastrophic thoughts about pain, self-efficacy, and psychological flexibility, will be assessed and statistically analyzed as mediators of hypothesized beneficial effects. The interventions' impacts on pain sensitivity and central sensitization will be investigated to test these physiological pathways as proximal drivers of PSP. To better characterize the patient experience, additional validated measures will be explored for associations with PSP, along with demographic and clinical factors. Trial registration: https://clinicaltrials.gov/ct2/show/NCT04225585, registered January 13, 2020.

Loss of E-cadherin Induces IGF1R Activation and Reveals a Targetable Pathway in Invasive Lobular Breast Carcinoma.

No special-type breast cancer [NST; commonly known as invasive ductal carcinoma (IDC)] and invasive lobular carcinoma (ILC) are the two major histological subtypes of breast cancer with significant differences in clinicopathological and molecular characteristics. The defining pathognomonic feature of ILC is loss of cellular adhesion protein, E-cadherin (CDH1). We have previously shown that E-cadherin functions as a negative regulator of the IGF1R and propose that E-cadherin loss in ILC sensitizes cells to growth factor signaling that thus alters their sensitivity to growth factor-signaling inhibitors and their downstream activators. To investigate this potential therapeutic vulnerability, we generated CRISPR-mediated CDH1 knockout (CDH1 KO) IDC cell lines (MCF7, T47D, and ZR75.1) to uncover the mechanism by which loss of E-cadherin results in IGF pathway activation. CDH1 KO cells demonstrated enhanced invasion and migration that was further elevated in response to IGF1, serum and collagen I. CDH1 KO cells exhibited increased sensitivity to IGF resulting in elevated downstream signaling. Despite minimal differences in membranous IGF1R levels between wild-type (WT) and CDH1 KO cells, significantly higher ligand-receptor interaction was observed in the CDH1 KO cells, potentially conferring enhanced downstream signaling activation. Critically, increased sensitivity to IGF1R, PI3K, Akt, and MEK inhibitors was observed in CDH1 KO cells and ILC patient-derived organoids. IMPLICATIONS: Overall, this suggests that these targets require further exploration in ILC treatment and that CDH1 loss may be exploited as a biomarker of response for patient stratification.

Timely cancer genetic counseling and testing for young women with breast cancer: impact on surgical decision-making for contralateral risk-reducing mastectomy.

PURPOSE: Genetic testing (GT) can identify individuals with pathogenic/likely pathogenic variants (PV/LPVs) in breast cancer (BC) predisposition genes, who may consider contralateral risk-reducing mastectomy (CRRM). We report on CRRM rates in young women newly diagnosed with BC who received GT through a multidisciplinary clinic. METHODS: Clinical data were reviewed for patients seen between November 2014 and June 2019. Patients with non-metastatic, unilateral BC diagnosed at age ≤ 45 and completed GT prior to surgery were included. Associations between surgical intervention and age, BC stage, family history, and GT results were evaluated. RESULTS: Of the 194 patients, 30 (15.5%) had a PV/LPV in a BC predisposition gene (ATM, BRCA1, BRCA2, CHEK2, NBN, NF1), with 66.7% in BRCA1 or BRCA2. Of 164 (84.5%) uninformative results, 132 (68%) were negative and 32 (16.5%) were variants of uncertain significance (VUS). Overall, 67 (34.5%) had CRRM, including 25/30 (83.3%) PV/LPV carriers and 42/164 (25.6%) non-carriers. A positive test result (p < 0.01) and significant family history were associated with CRRM (p = 0.02). For the 164 with uninformative results, multivariate analysis showed that CRRM was not associated with age (p = 0.23), a VUS, (p = 0.08), family history (p = 0.10), or BC stage (p = 0.11). CONCLUSION: In this cohort of young women with BC, the identification of a PV/LPV in a BC predisposition gene and a significant family history were associated with the decision to pursue CRRM. Thus, incorporation of genetic services in the initial evaluation of young patients with a new BC could contribute to the surgical decision-making process.