Long-term outcomes by lobular versus ductal histology in four NSABP adjuvant breast cancer trials.

We evaluated differences in long-term outcomes of invasive lobular carcinoma (ILC) vs breast cancers of no special type (NST) treated with anthracycline-based adjuvant chemotherapy using 4 National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized phase III trials (B-22, B-25, B-28, B-30). Our cohort included 11,251 patients with NST and 1,231 with ILC. Patients with ILC were older, had larger and more often estrogen receptor-positive tumors, and more positive lymph nodes. During early follow-up (0-5 years), patients with ILC had fewer recurrences (HR: 0.797; 95% confidence interval [CI] 0.685-0.929) and deaths (HR: 0.756; 95% CI 0.623-0.917). After 5 years patients with ILC had more recurrences (HR: 1.30; 95% CI 1.085-1.558) and deaths (HR: 1.044; 95% CI 0.898-1.214). Conditional probability analysis showed significant interactions between time-period and histologic type for recurrences (p < .001) and deaths (p < .001). Patients with ILC have elevated risk of late recurrence and death compared to patients with NST.

Electronic Health Record-Based Nudge Intervention and Axillary Surgery in Older Women With Breast Cancer: A Nonrandomized Controlled Trial.

Importance: Choosing Wisely recommendations advocate against routine use of axillary staging in older women with early-stage, clinically node-negative (cN0), hormone receptor-positive (HR+), and HER2-negative breast cancer. However, rates of sentinel lymph node biopsy (SLNB) in this population remain persistently high. Objective: To evaluate whether an electronic health record (EHR)-based nudge intervention targeting surgeons in their first outpatient visit with patients meeting Choosing Wisely criteria decreases rates of SLNB. Design, Setting, and Participants: This nonrandomized controlled trial was a hybrid type 1 effectiveness-implementation study with subsequent postintervention semistructured interviews and lasted from October 2021 to October 2023. Data came from EHRs at 8 outpatient clinics within an integrated health care system; participants included 7 breast surgical oncologists. Data were collected for female patients meeting Choosing Wisely criteria for omission of SLNB (aged ≥70 years with cT1 and cT2, cN0, HR+/HER2- breast cancer). The study included a 12-month preintervention control period; baseline surveys assessing perceived acceptability, appropriateness, and feasibility of the designed intervention; and a 12-month intervention period. Intervention: A column nudge was embedded into the surgeon's schedule in the EHR identifying patients meeting Choosing Wisely criteria for potential SLNB omission. Main Outcomes and Measures: The primary outcome was rate of SLNB following nudge deployment into the EHR. Results: Similar baseline demographic and tumor characteristics were observed before (control period, n = 194) and after (intervention period, n = 193) nudge deployment. Patients in both the control and intervention period had a median (IQR) age of 75 (72-79) years. Compared with the control period, unadjusted rates of SLNB decreased by 23.1 percentage points (46.9% SLNB rate prenudge to 23.8% after; 95% CI, -32.9 to -13.8) in the intervention period. An interrupted time series model showed a reduction in the rate of SLNB following nudge deployment (adjusted odds ratio, 0.26; 95% CI, 0.07 to 0.90; P = .03). The participating surgeons scored the intervention highly on acceptability, appropriateness, and feasibility. Dominant themes from semistructured interviews indicated that the intervention helped remind the surgeons of potential Choosing Wisely applicability without the need for additional clicks or actions on the day of the patient visit, which facilitated use. Conclusions and Relevance: This study showed that a nudge intervention in the EHR significantly decreased low-value axillary surgery in older women with early-stage, cN0, HR+/HER2- breast cancer. This user-friendly and easily implementable EHR-based intervention could be a beneficial approach for decreasing low-value care in other practice settings or patient populations. Trial Registration: ClinicalTrials.gov Identifier: NCT06006910.

Mutual information for detecting multi-class biomarkers when integrating multiple bulk or single-cell transcriptomic studies.

Motivation: Biomarker detection plays a pivotal role in biomedical research. Integrating omics studies from multiple cohorts can enhance statistical power, accuracy and robustness of the detection results. However, existing methods for horizontally combining omics studies are mostly designed for two-class scenarios (e.g., cases versus controls) and are not directly applicable for studies with multi-class design (e.g., samples from multiple disease subtypes, treatments, tissues, or cell types). Results: We propose a statistical framework, namely Mutual Information Concordance Analysis (MICA), to detect biomarkers with concordant multi-class expression pattern across multiple omics studies from an information theoretic perspective. Our approach first detects biomarkers with concordant multi-class patterns across partial or all of the omics studies using a global test by mutual information. A post hoc analysis is then performed for each detected biomarkers and identify studies with concordant pattern. Extensive simulations demonstrate improved accuracy and successful false discovery rate control of MICA compared to an existing MCC method. The method is then applied to two practical scenarios: four tissues of mouse metabolism-related transcriptomic studies, and three sources of estrogen treatment expression profiles. Detected biomarkers by MICA show intriguing biological insights and functional annotations. Additionally, we implemented MICA for single-cell RNA-Seq data for tumor progression biomarkers, highlighting critical roles of ribosomal function in the tumor microenvironment of triple-negative breast cancer and underscoring the potential of MICA for detecting novel therapeutic targets. Availability: https://github.com/jianzou75/MICA.

Use of Natural Language Understanding to Facilitate Surgical De-Escalation of Axillary Staging in Patients With Breast Cancer.

PURPOSE: Natural language understanding (NLU) may be particularly well equipped for enhanced data capture from the electronic health record given its examination of both content-driven and context-driven extraction. METHODS: We developed and applied a NLU model to examine rates of pathological node positivity (pN+) and rates of lymphedema to determine whether omission of routine axillary staging could be extended to younger patients with estrogen receptor-positive (ER+)/cN0 disease. RESULTS: We found that rates of pN+ and arm lymphedema were similar between patients age 55-69 years and ≥70 years, with rates of lymphedema exceeding rates of pN+ for clinical stage T1c and smaller disease. CONCLUSION: Data from our NLU model suggest that omission of sentinel lymph node biopsy might be extended beyond Choosing Wisely recommendations, limited to those older than 70 years and 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.

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.

The Great Immune Escape: Understanding the Divergent Immune Response in Breast Cancer Subtypes.

Breast cancer, the most common type of cancer affecting women, encompasses a collection of histologic (mainly ductal and lobular) and molecular subtypes exhibiting diverse clinical presentation, disease trajectories, treatment options, and outcomes. Immunotherapy has revolutionized treatment for some solid tumors but has shown limited promise for breast cancers. In this review, we summarize recent advances in our understanding of the complex interactions between tumor and immune cells in subtypes of breast cancer at the cellular and microenvironmental levels. We aim to provide a perspective on opportunities for future immunotherapy agents tailored to specific features of each subtype of breast cancer. SIGNIFICANCE: Although there are currently over 200 ongoing clinical trials testing immunotherapeutics, such as immune-checkpoint blockade agents, these are largely restricted to the triple-negative and HER2+ subtypes and primarily focus on T cells. With the rapid expansion of new in vitro, in vivo, and clinical data, it is critical to identify and highlight the challenges and opportunities unique for each breast cancer subtype to drive the next generation of treatments that harness the immune system.

Case report: abemaciclib-induced syndrome of inappropriate antidiuretic hormone (SIADH) without underlying kidney injury in a patient with early-stage estrogen receptor (ER)+ breast cancer.

The CDK4/6 inhibitor, abemaciclib, is now the standard of care adjuvant therapy for patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) tumors at high risk of recurrence. Real-world usage uncovers emerging side effects that may have been previously unreported in clinical trials. Here, we present the clinical course of a patient who developed a syndrome of inappropriate antidiuretic hormone (SIADH) without underlying kidney injury due to abemaciclib use.

Clinicopathological Features and Outcomes Comparing Patients With Invasive Ductal and Lobular Breast Cancer.

BACKGROUND: There is increasing interest in better understanding the biology and clinical presentation of invasive lobular cancer (ILC), which is the most common special histological subtype of breast cancer. Limited large contemporary data sets are available allowing comparison of clinicopathologic features between ILC and invasive ductal cancer (IDC). METHODS: The Great Lakes Breast Cancer Consortium was formed to compare clinical behavior of ILC (n = 3617) and IDC (n = 30 045) from 33 662 patients treated between 1990 and 2017 at 3 large clinical centers. We used Kaplan-Meier analysis, Cox proportional hazards modeling, and propensity score matching to evaluate treatment differences and outcomes. All statistical testing used 2-sided P values. RESULTS: Compared with IDC, patients with ILC were more frequently diagnosed at later stages and with more lymph node involvement (corrected P < .001). Estrogen receptor-positive ILCs were of lower grade (grade 1 and 2: 90% in ILC vs 72% in IDC) but larger in size (T3 and 4: 14.3% in ILC vs 3.4% in IDC) (corrected P < .001), and since 1990, the mean ILC size detected at diagnosis increased yearly. Patients with estrogen receptor (ER)-positive ILC underwent statistically significantly more mastectomies compared with ER-positive IDC (57% vs 46%). Using Kaplan-Meier analysis, patients with ER-positive ILC had statistically significantly worse disease-free survival and overall survival than ER-positive IDC although 6 times more IDCs were classified as high risk by OncotypeDx Breast Recurrence Score assay. CONCLUSIONS: This large, retrospective, collaborative analysis with 3 clinical centers identified meaningful differences in clinicopathological features between ILC and IDC, providing further evidence that these are 2 different entities requiring different clinical management.

Predoctoral MD-PhD grants as indicators of future NIH funding success.

MD-PhD trainees constitute an important source of physician-scientists. Persistence on this challenging path is facilitated by success in garnering independent (R grant) support from the NIH. Published research tracks academic appointments and global R01 success for MD-PhD trainees but has not included information on future funding success of individual MD-PhD predoctoral grant holders. Here, we used data from the NIH RePORTER database to identify and track the funding trajectory of physician-scientists who received predoctoral grant support through the F30 mechanism, which is specific for dual-degree candidates. Male and female F30 awardees did not differ in their success in garnering K (postdoctoral training) grants, but, among F30 grant awardees, men were 2.6 times more likely than women to receive R funding. These results underscore the need for analysis of factors that contribute to the disproportionate loss of NIH-supported female physician-scientists between the predoctoral F30 and the independent R grant-supported stages.

Personalising therapy for early-stage oestrogen receptor-positive breast cancer in older women.

Age is one of the most important risk factors for the development of breast cancer. Nearly a third of all breast cancer cases occur in older women (aged ≥70 years), with most cases being oestrogen receptor-positive (ER+). Such tumours are often indolent and unlikely to be the ultimate cause of death for older women, particularly when considering other comorbidities. This Review focuses on unique clinical considerations for screening, detection, and treatment regimens for older women who develop ER+ breast cancers-specifically, we focus on recent trends for de-implementation of screening, staging, surgery, and adjuvant therapies along the continuum of care. Additionally, we also review emerging basic and translational research that will further uncover the unique underlying biology of these tumours, which develop in the context of systemic age-related inflammation and changing hormone profiles. With prevailing trends of clinical de-implementation, new insights into mechanistic biology might provide an opportunity for precision medicine approaches to treat patients with well tolerated, low-toxicity agents to extend patients' lives with a higher quality of life, prevent tumour recurrences, and reduce cancer-related burdens.

Association Between Portal Vein Thrombosis and Pouchitis in Patients with Ulcerative Colitis.

BACKGROUND: Pouchitis is the most common long-term complication in patients requiring colectomy ileal pouch-anal anastomosis with medically refractory ulcerative colitis or colitis-associated neoplasia. A previous small case series suggests associated between portal vein thrombosis (PVT) and ischemic pouchitis. AIM: To evaluate the association between PVT and other demographic and clinical factors and pouchitis. METHODS: We used Explorys Inc., a population-based database, to search medical records between 1999 and 2020 with SNOMED-CT code criteria for "construction of pouch" and "ileal pouchitis." Patients with pouchitis were compared to those with previous pouch construction without pouchitis. Factors associated with pouchitis identified with univariable analysis were introduced into a multivariable model. A post hoc analysis further stratified demographical findings of the association between PVT and pouchitis. RESULTS: We identified 7900 patients with ileal pouchitis (7.5%) and 97,510 with pouch construction without pouchitis. In multivariate binary logistic regression, adjusted odds ratio (aOR) for the risk of pouchitis in patients with PVT was 10.78 (95% confidence interval [CI] 7.04-16.49, P < 0.001). Other significant factors associated with pouchitis included male gender (aOR 1.11, 95% CI 1.02-1.21, P = 0.018), deep vein thrombosis (aOR 1.46, 95% CI 1.23-1.72, P < 0.001), and the use of non-steroidal anti-inflammatory drugs (aOR 1.37, 95% CI 1.28-1.45, P < 0.001). Smoking was a protective factor (aOR 0.30, 95% CI 0.33-0.36, P < 0.001). Further sub-analysis showed a higher prevalence of younger patients with PVT and pouchitis. CONCLUSIONS: We report PVT as an independent risk factor associated with pouchitis. Our findings support that PVT is a potentially manageable perioperative complication, and intervention may reduce the risk of pouchitis.

MALT1 Is a Targetable Driver of Epithelial-to-Mesenchymal Transition in Claudin-Low, Triple-Negative Breast Cancer.

MALT1 is the effector protein of the CARMA/Bcl10/MALT1 (CBM) signalosome, a multiprotein complex that drives pro-inflammatory signaling pathways downstream of a diverse set of receptors. Although CBM activity is best known for its role in immune cells, emerging evidence suggests that it plays a key role in the pathogenesis of solid tumors, where it can be activated by selected G protein-coupled receptors (GPCR). Here, we demonstrated that overexpression of GPCRs implicated in breast cancer pathogenesis, specifically the receptors for Angiotensin II and thrombin (AT1R and PAR1), drove a strong epithelial-to-mesenchymal transition (EMT) program in breast cancer cells that is characteristic of claudin-low, triple-negative breast cancer (TNBC). In concert, MALT1 was activated in these cells and contributed to the dramatic EMT phenotypic changes through regulation of master EMT transcription factors including Snail and ZEB1. Importantly, blocking MALT1 signaling, through either siRNA-mediated depletion of MALT1 protein or pharmacologic inhibition of its activity, was effective at partially reversing the molecular and phenotypic indicators of EMT. Treatment of mice with mepazine, a pharmacologic MALT1 inhibitor, reduced growth of PAR1+, MDA-MB-231 xenografts and had an even more dramatic effect in reducing the burden of metastatic disease. These findings highlight MALT1 as an attractive therapeutic target for claudin-low TNBCs harboring overexpression of one or more selected GPCRs. IMPLICATIONS: This study nominates a GPCR/MALT1 signaling axis as a pathway that can be pharmaceutically targeted to abrogate EMT and metastatic progression in TNBC, an aggressive form of breast cancer that currently lacks targeted therapies.

Strategies for Achieving Gender Equity and Work-Life Integration in Physician-Scientist Training.

Substantial gender inequities persist across academic medicine. These issues are not new: Recent evidence still points to a chilly climate for women in academic medicine, including those in physician-scientist training. The discussion for how to address gender equity and issues of work-life integration typically centers around faculty and rarely includes trainees. The authors delineate specific strategies to address gender inequity in physician-scientist training by identifying key stakeholders for implementation and proposing areas to integrate these strategies with current training timelines. Strategies discussed include multiple-role mentoring, allyship training for trainees and faculty, early implementation of professional development sessions, incorporation of childcare and family-friendly policies, and additional policies for funding bodies to prioritize gender equity practices. The goal of this article is to equip trainees and the academic community with proactive strategies to create a more equitable environment for future generations of trainees in academic medicine.

Outcomes After Sentinel Lymph Node Biopsy and Radiotherapy in Older Women With Early-Stage, Estrogen Receptor-Positive Breast Cancer.

Importance: Overtreatment of early-stage breast cancer with favorable tumor biology in older patients may be harmful without affecting recurrence and survival. Guidelines that recommend deimplementation of sentinel lymph node biopsy (SLNB) (Choosing Wisely) and radiotherapy (RT) (National Comprehensive Cancer Network) have been published. Objective: To describe the use rates and association with disease recurrence of SLNB and RT in older women with breast cancer. Design, Setting, and Participants: This cohort study obtained patient and clinical data from an integrated cancer registry and electronic health record of a single health care system in Pennsylvania. The cohort was composed of consecutive female patients 70 years or older who were diagnosed with early-stage, estrogen receptor-positive, ERBB2 (formerly HER2)-negative, clinically node-negative breast cancer from January 1, 2010, to December 31, 2018, who were treated at 15 community and academic hospitals within the health system. Exposures: Sentinel lymph node biopsy and adjuvant RT. Main Outcomes and Measures: Primary outcomes were 5-year locoregional recurrence-free survival (LRFS) rate and disease-free survival (DFS) rate after SLNB and after RT. Secondary outcomes included recurrence rate, subgroups that may benefit from SLNB or RT, and use rate of SLNB and RT over time. Propensity scores were used to create 2 cohorts to separately evaluate the association of SLNB and RT with recurrence outcomes. Cox proportional hazards regression model was used to estimate hazard ratios (HRs). Results: From 2010 to 2018, a total of 3361 women 70 years or older (median [interquartile range {IQR}] age, 77.0 [73.0-82.0] years) with estrogen receptor-positive, ERBB2-negative, clinically node-negative breast cancer were included in the study. Of these women, 2195 (65.3%) received SLNB and 1828 (54.4%) received adjuvant RT. Rates of SLNB steadily increased (1.0% per year), a trend that persisted after the 2016 adoption of the Choosing Wisely guideline. Rates of RT decreased slightly (3.4% per year). To examine patient outcomes and maximize follow-up time, the analysis was limited to cases from 2010 to 2014, identifying 2109 patients with a median (IQR) follow-up time of 4.1 (2.5-5.7) years. In the propensity score-matched cohorts, no association was found between SLNB and either LRFS (HR, 1.26; 95% CI, 0.37-4.30; P = .71) or DFS (HR, 1.92; 95% CI, 0.86-4.32; P = .11). In addition, RT was not associated with LRFS (HR, 0.33; 95% CI, 0.09-1.24; P = .10) or DFS (HR, 0.99; 95% CI, 0.46-2.10; P = .97). Subgroup analysis showed that stratification by tumor grade or comorbidity was not associated with LRFS or DFS. Low absolute rates of recurrence were observed when comparing the groups that received SLNB (3.5%) and those that did not (4.5%) as well as the groups that received RT (2.7%) and those that did not (5.5%). Conclusions and Relevance: This study found that receipt of SLNB or RT was not associated with improved LRFS or DFS in older patients with ER-positive, clinically node-negative breast cancer. Despite limited follow-up time and wide 95% CIs, this study supports the continued deimplementation of both SLNB and RT in accordance with the Choosing Wisely and National Comprehensive Cancer Network guidelines.