Clinicopathological characteristics and eligibility for adjuvant olaparib of germline BRCA1/2 mutation carriers with HER2-negative early breast cancer.

Following the survival benefit demonstrated in the OlympiA trial, one year of adjuvant olaparib is now recommended for all patients with germline BRCA1/2 pathogenic/likely pathogenic variants (PV) and high-risk, HER2-negative early breast cancer after chemotherapy. However, optimal identification of high-risk patients who may derive benefit from this genomically-directed therapy is debated. In this study, we sought to characterize the real-world proportion of gBRCA1/2 PV carriers eligible for adjuvant olaparib according to the OlympiA criteria, and to compare clinicopathologic characteristics and outcomes between eligible and ineligible patients.

Evolution of HER2 expression between pre-treatment biopsy and residual disease after neoadjuvant therapy for breast cancer.

INTRODUCTION: We have previously found that HER2 expression is dynamic, and can change from the primary breast tumor to matched recurrences. With this work, we aimed to assess the dynamics of HER2 during neoadjuvant treatment.(NAT). METHODS: We reviewed HER2 expression in pre- and post-treatment samples from consecutive patients with early-stage breast cancer that received NAT and underwent surgery at Dana-Farber Brigham Cancer Center between 01/2016-08/2022. The primary outcome was evolution of HER2 expression from pre- to post-NAT specimens in patients with residual disease. RESULTS: Among 1613 patients receiving NAT, 1080 had residual disease at surgery. A total of 319 patients (29.5%) experienced a change in HER2 expression (HER2 0 vs. HER2-low vs. HER2-positive) from the pre-treatment sample to residual disease, with roughly equal distribution between decreased (50.5%) and increased HER2 expression (49.5%). Similar rates of change in HER2 expression were observed with anthracycline-based (31.8%) or taxane/platinum-based regimens (32.4%). Patients with HER2-0 or HER2-low tumors at diagnosis were likelier to experience a change in HER2 expression post-NAT compared to HER2-positive (32.3% vs. 21.3%, p < 0.001). Changes in HER2 expression post-NAT were prognostic among patients with HER2-positive tumors at diagnosis (3-year recurrence-free survival for change vs. no change: 71.6% vs. 89.6%, p = 0.006) but not among those with HER2-negative tumors at diagnosis (3-year recurrence-free survival for change vs. no change: 79.3% vs. 81.1%, p = 0.31). CONCLUSIONS: Nearly 30% of patients with early-stage breast cancer showed a change in HER2 expression after NAT. Changes in HER2 expression post-NAT were only prognostic in the setting of HER2-positive tumors becoming HER2-negative at surgery.

Upgrade Rates and Breast Cancer Development Among Germline Pathogenic Variant Carriers with High-Risk Breast Lesions.

BACKGROUND: High-risk lesions (HRL) of the breast are risk factors for future breast cancer development and may be associated with a concurrent underlying malignancy when identified on needle biopsy; however, there are few data evaluating HRLs in carriers of germline pathogenic variants (PVs) in breast cancer predisposition genes. METHODS: We identified patients from two institutions with germline PVs in high- and moderate-penetrance breast cancer predisposition genes and an HRL in an intact breast, including atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), and lobular neoplasia (LN). We calculated upgrade rates at surgical excision and used Kaplan-Meier methods to characterize 3-year breast cancer risk in patients without upgrade. RESULTS: Of 117 lesions in 105 patients, 65 (55.6%) were ADH, 48 (41.0%) were LN, and 4 (3.4%) were FEA. Most PVs (83.8%) were in the BRCA1/2, CHEK2 and ATM genes. ADH and FEA were excised in most cases (87.1%), with upgrade rates of 11.8% (95% confidence interval [CI] 5.5-23.4%) and 0%, respectively. LN was selectively excised (53.8%); upgrade rate in the excision group was 4.8% (95% CI 0.8-22.7%), and with 20 months of median follow-up, no same-site cancers developed in the observation group. Among those not upgraded, the 3-year risk of breast cancer development was 13.1% (95% CI 6.3-26.3%), mostly estrogen receptor-positive (ER +) disease (89.5%). CONCLUSIONS: Upgrade rates for HRLs in patients with PVs in breast cancer predisposition genes appear similar to non-carriers. HRLs may be associated with increased short-term ER+ breast cancer risk in PV carriers, warranting strong consideration of surgical or chemoprevention therapies in this population.

Prevalence, Dynamics, and Prognostic Role of Clonal Hematopoiesis of Indeterminate Potential in Patients With Breast Cancer.

PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is frequent in patients with solid tumors. Prospective data about CHIP prevalence at breast cancer diagnosis and its dynamic evolution under treatment selective pressure are limited. PATIENTS AND METHODS: We performed targeted error-corrected sequencing on 614 samples from 380 patients with breast cancer. We investigated the dynamics of CHIP on prospectively collected paired samples from patients with early breast cancer (eBC) receiving chemotherapy (CT) or endocrine therapy (ET). We assessed the correlation of CHIP with survival in patients with metastatic triple-negative breast cancer (mTNBC). We estimated the risk of progression to treatment-related myeloid neoplasms (t-MN) according to the clonal hematopoiesis risk score (CHRS). In exploratory analyses, we considered clonal hematopoiesis (CH) with variant allele fraction (VAF) ≥0.005. RESULTS: CHIP was identified in 15% of patients before treatment. Few CHIP emerged after treatment, and the risk of developing new mutations was similar for patients receiving CT versus ET (odds ratio [OR], 1.16; P = .820). However, CT increased the risk of developing new CH with VAF ≥0.005 (OR, 3.45; P = .002). Five TP53-mutant CH with VAF ≥0.005 emerged among patients receiving CT. Most patients had low risk of t-MN according to the CHRS score. CHIP did not correlate with survival in mTNBC. CONCLUSION: CHIP is frequent in patients with breast cancer. In this study, CT did not lead to emergence of new CHIP, and most patients had low risk of developing t-MN. This finding is reassuring, given long life expectancy of patients with eBC and the association of CHIP with morbidity and mortality. However, TP53-mutant CH with VAF ≥0.005 emerged with CT, which carries high risk of t-MN. Evolution of these small clones and their clinical significance warrant further investigation.

Development of an Electronic Health Record Registry to Facilitate Collection of Commission on Cancer Metrics for Patients Undergoing Surgery for Breast Cancer.

PURPOSE: Accurate and efficient data collection is a challenge for quality improvement initiatives and clinical research. We describe the development of a custom electronic health record (EHR)-based registry to automatically extract structured Commission on Cancer axillary surgery-specific metrics from a custom synoptic note template included in the operative reports for patients with breast cancer undergoing surgery. METHODS: The smart functionality of our enterprise-based EHR system was leveraged to create a custom smart phrase to capture axillary surgery-specific variables. A multidisciplinary team developed structured data elements correlating to each axillary surgery-specific variable. These data elements were then included in a note template for the operative report. Each variable could be aggregated and converted into a single flat database through the EHR's reporting workbench and serve as a live, prospective registry for all users within the EHR. RESULTS: The final axillary surgery-specific note template in a synoptic format allowed for efficient and easy entry and automatic collection of breast cancer-specific metrics. From initial adoption in February 2021-December 2021, there were 1,254 patients who underwent breast surgery with axillary surgery. The operative notes allowed for automatic capture of metrics from 60.5% (n = 759) of patients. Data capture improved from 37.6% in the initial adoption period of 6 months to 86.2% in the last 5 months. CONCLUSION: We were able to demonstrate successful implementation of provider-driven structured data entry into EHR systems that permits automatic data capture. The end result is a custom synoptic note template and a real-time, prospective registry of breast cancer-specific Commission on Cancer metrics that are robust enough to use for quality improvement initiatives and clinical research.

Rates of pathologic nodal disease among cN0 and cN1 patients undergoing routine axillary ultrasound and neoadjuvant chemotherapy.

PURPOSE: Routine axillary ultrasound (AxUS) in patients receiving neoadjuvant chemotherapy (NAC) remains controversial. Here, we report rates of AxUS-detected nodal disease among patients with normal clinical exams, and rates of pathologic nodal disease after NAC based on method of nodal disease detection. METHODS: Clinicopathologic findings were prospectively collected for stage I-III breast cancer patients selected for NAC. All patients had pre-treatment AxUS, suspicious nodes were biopsied. The following four patient cohorts were examined: patients with suspicious exam or AxUS but negative biopsy (Suspicious cN0); those with normal exam and normal AxUS (Not Suspicious cN0); those with normal exam but suspicious AxUS and positive biopsy (AxUS-detected cN1); and those with abnormal exam and positive biopsy (exam-detected cN1). Sentinel (SLN) and non-sentinel lymph nodes (non-SLN) were evaluated by immunohistochemistry; nodal metastases of any size were considered positive. RESULTS: 500 patients were included. Of 310 patients with normal axillary exams, 160 had suspicious AxUS, 65 were biopsy-negative (Suspicious cN0) and 95/310 (30.6%) were biopsy-positive (AxUS-detected cN1). Of 190 with abnormal axillary exams, 166 were biopsy-proven node-positive (exam-detected cN1) and 24 were AxUS or biopsy-negative (Suspicious cN0). Rates of pathologic nodal disease were 20/150 (13.3%) among Not Suspicious cN0 patients, 12/89 (13.5%) among Suspicious cN0 (p = 0.97). Rates of residual nodal disease were 55/95 (57.9%) among AxUS-detected cN1 patients, 102/166 (61.4%) among exam-detected cN1 (p = 0.57). CONCLUSION: AxUS detected nodal disease in 30.6% of patients with normal clinical exams selected for NAC. Rates of pathologic nodal disease were similar among AxUS-detected and exam-detected cN1 patients.

Prognostic and Biologic Significance of ERBB2-Low Expression in Early-Stage Breast Cancer.

Importance: It is unclear whether ERBB2-low breast cancer should be considered an individual biologic subtype distinct from ERBB2-0 breast cancer. Objective: To investigate whether low ERBB2 expression is associated with distinct clinicopathologic characteristics and prognosis among patients with hormone receptor (HR)-positive and triple-negative breast cancer (TNBC). Design, Setting, and Participants: This cohort study was conducted using data from a prospectively maintained institutional database on all consecutive patients with breast cancer undergoing surgery between January 2016 and March 2021 at Dana-Farber Brigham Cancer Center. The study included 5235 patients with stage I through III, ERBB2-negative invasive breast cancer. Tumors were classified as ERBB2-low if they had an ERBB2 immunohistochemical (IHC) score of 1+ or 2+ with negative in situ hybridization assay and ERBB2-0 if they had an ERBB2 IHC score of 0. Data were analyzed from September 2021 through January 2022. Exposures: Standard treatment according to institutional guidelines. Main Outcomes and Measures: Comparison of clinicopathologic characteristics and disease outcomes (pathologic complete response rate [pCR], disease-free survival, distant disease-free survival, and overall survival) between patients with ERBB2-low and ERBB2-0 breast cancer. Results: Among 5235 patients with ERBB2-negative invasive breast cancer (5191 [99.2%] women; median [range] age at primary surgery, 59.0 [21.0-95.0] years), 2917 patients (55.7%) and 2318 patients (44.3%) had ERBB2-low and ERBB2-0 tumors, respectively. Expression of HR was significantly more common among ERBB2-low compared with ERBB2-0 tumors (2643 patients [90.6%] vs 1895 patients [81.8%]; P < .001). The rate of ERBB2-low tumors increased progressively, from 296 of 739 estrogen receptor (ER)-negative tumors (40.1%) to 31 of 67 ER-low (ie, ER 1%-9%) tumors (46.3%), 37 of 67 ER-moderate (ie, ER, 10%-49%) tumors (55.2%), 2047 of 3542 ER-high (ie, ER, 50%-95%) tumors (57.8%), and 499 of 803 ER-very high (ie, ER > 95%) tumors (62.1%) (P < .001). Among 675 patients receiving neoadjuvant chemotherapy, those with ERBB2-0 tumors experienced higher pCR rates (95 patients [26.8%] vs 53 patients [16.6%]; P = .002). However, there were no statistically significant differences in pCR rate between ERBB2-low and ERBB2-0 tumors when separately analyzing HR-positive, ER-low, HR-positive without ER-low, or TNBC tumors. In exploratory survival analysis, no differences by ERBB2-low expression in disease-free survival, distant disease-free survival, or overall survival were observed among patients with HR-positive tumors or TNBC. Conclusions and Relevance: The results of this cohort study did not support the interpretation of ERBB2-low breast cancer as a distinct biologic subtype. ERBB2-low expression was positively associated with level of ER expression, and ER-low tumors were enriched among ERBB2-0 tumors, suggesting that, given the worse prognosis of ER-low tumors, they may be associated with confounding of prognostic analyses of ERBB2-low expression.

Practice Improvement for Standardized Evaluation and Management of Acute Tracheitis in Mechanically Ventilated Children.

There is no consensus definition for ventilator-associated tracheitis and limited evidence to guide diagnosis and treatment. To improve acute tracheitis evaluation and management, this quality improvement project aimed to (1) improve the appropriateness of tracheal aspirate cultures while decreasing the number of unnecessary cultures by 20% and (2) decrease antibiotic use for acute tracheitis not consistent with local guidelines by 20% over 12 months among pediatric patients requiring mechanical ventilation. METHODS: All patients admitted to the Medical Intensive Care Unit requiring mechanical ventilation via an artificial airway were included. Tracheal aspirate sampling criteria, technique, and minimum intervals were standardized. Primary outcome measures were the number of tracheal aspirate cultures obtained per 100 ETT/tracheostomy days and ventilator-associated antibiotic days per 100 ETT/tracheostomy days. Improvement cycles included: Implementation of tracheal aspirate sampling criteria, sampling technique standardization, limiting repeat cultures to >72-hour intervals, and standardizing empiric antibiotic therapy. RESULTS: Tracheal aspirate culture rate decreased from 10.70 to 7.10 cultures per 100 ETT/tracheostomy days (P < 0.001). Cultures meeting sampling criteria increased from 28% to 80%. Ventilator-associated antibiotic use decreased from 24.88 to 7.30 ventilator-associated antibiotic days per 100 ETT/tracheostomy days. There were no associated increases in ventilator-associated events or days of mechanical ventilation. CONCLUSIONS: Implementation of standardized criteria for tracheal aspirate sampling, improved tracheal aspirate sampling technique, limiting repeat tracheal aspirate cultures, and utilizing standardized antibiotic treatment guidelines safely decreased resource utilization and antibiotic use among critically ill children requiring mechanical ventilation.

Quality Improvement Incorporating a Feedback Loop for Accurate Medication Reconciliation.

OBJECTIVES: Medication reconciliation errors on hospital admission can lead to significant patient harm. A pediatric intermediate care unit initiated a quality improvement project and aimed to reduce errors in admission medication reconciliation by 50% in 12 months. METHODS: From August 2017 to December 2018, a multidisciplinary team conducted a quality improvement project with plan-do-study-act methodology. Continuous data collection was achieved by reviewing medications with home caregivers within 18 hours of admission to identify errors. Cycle 1 consisted of nursing training in accurate and thorough medication history documentation. Cycle 2 was aimed at improving data collection. Cycle 3 was aimed at improving pediatric housestaff processes for medication reconciliation. In cycle 4 intervention, the reconciliation process was redesigned to incorporate the bedside nurse reviewing final medication orders with the patient's home caregivers once the medication reconciliation process was complete. Intermittent maintenance data collection continued for 12 months thereafter. RESULTS: Cycle 1 and 2 interventions resulted in improvement in the medication reconciliation error rate from 9.8% to 4.7%. In cycle 2, the data collection rate improved from 61% to 80% of admissions sustained. Cycle 3 resulted in a further reduction in the medication error rate to 2.9%, which was sustained in cycle 4 and over the 12-month maintenance period. A patient's number of home medications did not correlate with the error rate. CONCLUSIONS: Reductions in admission medication reconciliation errors can be achieved with staff education on medication history and process for medication reconciliation and with process redesign that incorporates active medication order review as a closed-loop communication with home caregivers.

Global Gaps in Training Opportunities for Pediatricians and Pediatric Subspecialists.

OBJECTIVE: A comprehensive, well-trained pediatric workforce is needed to ensure high-quality child health interventions around the globe. Further understanding of pediatric workforce training capacity would assist planning at the global and country level. The purpose of this study was to better understand the availability and process of training programs for pediatricians and pediatric subspecialists worldwide, as well as in-country presence of subspecialists. METHODS: A survey was developed and distributed by e-mail to national pediatric leaders across the globe. The survey asked about the number of pediatric training programs, duration and logistics of training, and whether practicing pediatric subspecialists and subspecialty training programs were available in their country. RESULTS: We received responses from 121 of the 166 countries contacted (73%). Of these, 108 countries reported the presence of one or more general pediatric postgraduate training programs, ranging from 1 to 500 programs per country. The number of training programs did not vary significantly by gross domestic product but did vary by region, with the fewest in Africa (P < .001). Most countries identified national guidelines for training (82% of countries) and accreditation (84% of countries). Availability of pediatric subspecialists varied significantly by income and region, from no subspecialties available in 4 countries to all 26 queried subspecialties available in 17 countries. Neonatology was most common, available in 88% of countries. Subspecialty training programs were less available overall, significantly correlating with country income. CONCLUSION: Education for general pediatrics and pediatric subspecialties is quite limited in many of the countries surveyed, particularly in Africa. The creation of additional educational capacity is a critical issue challenging the adequate provision of pediatrics and pediatric subspecialty services.