Intratumoral Injection of mRNA-2752 and Pembrolizumab for High-Risk Ductal Carcinoma In Situ: A Phase 1 Nonrandomized Clinical Trial.

Importance: Intratumoral immunotherapy that leverages the biological characteristics of high-risk ductal carcinoma in situ (DCIS) may be able to reduce the extent of surgical treatment and provide an alternative approach to improve patient outcomes.

Objective: To determine if combination intratumoral immunotherapy can activate immune cells to shrink or eliminate high-risk DCIS.

Design, Setting, And Participants: This phase 1 open-label nonrandomized clinical trial at a single academic center tested the safety and efficacy of intratumoral immunotherapy in patients with high-risk DCIS, defined as at least 2 of the following present: younger than 45 years, tumor size greater than 5 cm, high-grade, palpable mass, hormone receptor (HR)-negative, or ERBB2-positive.

Hormone Receptor-Positive HER2-Negative/MammaPrint High-2 Breast Cancers Closely Resemble Triple-Negative Breast Cancers.

Purpose: The MammaPrint (MP) prognostic assay categorizes breast cancers into high- and low-risk subgroups, and the high-risk group can be further subdivided into high-1 (MP-H1), and very high-risk high-2 (MP-H2). The aim of this analysis was to assess clinical and molecular differences between the hormone receptor-positive (HR+)/HER2-negative MP-H1, -H2, and triple-negative (TN) MP-H1 and -H2 cancers.

Experimental Design: Pretreatment gene expression data from 742 HER2-negative breast cancers enrolled in the I-SPY2 neoadjuvant trial were used.

Multi-platform biomarkers of response to an immune checkpoint inhibitor in the neoadjuvant I-SPY 2 trial for early-stage breast cancer.

Only a subset of patients with breast cancer responds to immune checkpoint blockade (ICB). To better understand the underlying mechanisms, we analyze pretreatment biopsies from patients in the I-SPY 2 trial who receive neoadjuvant ICB using multiple platforms to profile the tumor microenvironment. A variety of immune cell populations and markers of immune/cytokine signaling associate with pathologic complete response (pCR).

Pathologic complete response (pCR) rates for patients with HR+/HER2- high-risk, early-stage breast cancer (EBC) by clinical and molecular features in the phase II I-SPY2 clinical trial.

Background: Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer (EBC) is a heterogenous disease. Identification of better clinical and molecular biomarkers is essential to guide optimal therapy for each patient.

Patients And Methods: We analyzed rates of pathologic complete response (pCR) and distant recurrence-free survival (DRFS) for patients with HR+/HER2-negative EBC in eight neoadjuvant arms in the I-SPY2 trial by clinical/molecular features: age, stage, histology, percentage estrogen receptor (ER) positivity, ER/progesterone receptor status, MammaPrint (MP)-High1 (0 to -0.

Datopotamab-deruxtecan plus durvalumab in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial.

Sequential adaptive trial designs can help accomplish the goals of personalized medicine, optimizing outcomes and avoiding unnecessary toxicity. Here we describe the results of incorporating a promising antibody-drug conjugate, datopotamab-deruxtecan (Dato-DXd) in combination with programmed cell death-ligand 1 inhibitor, durvalumab, as the first sequence of therapy in the I-SPY2.2 phase 2 neoadjuvant sequential multiple assignment randomization trial for high-risk stage 2/3 breast cancer.

Datopotamab-deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial.

Among the goals of patient-centric care are the advancement of effective personalized treatment, while minimizing toxicity. The phase 2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimizing individual outcomes.

Navigating inter-team competition: How information broker teams achieve team innovation.

Organizations are increasingly using teams to stimulate innovation. Often, these teams share knowledge and information with each other to help achieve their goals, while also competing for resources and striving to outperform each other. Importantly, based on their industry, the nature of work, or prior history, some teams may face more competition from peer teams than others.

Magnetic resonance imaging insights from active surveillance of women with ductal carcinoma in situ.

New approaches are needed to determine which ductal carcinoma in situ (DCIS) is at high risk for progression to invasive ductal carcinoma (IDC). We retrospectively studied DCIS patients who declined surgery (2002-2019), and received endocrine therapy (ET) and breast MRI. Baseline MRI and changes at 3 months and 6 months were analyzed by recursive partitioning to stratify IDC risk.

Tumor microenvironmental determinants of high-risk DCIS progression.

Ductal carcinoma (DCIS) constitutes an array of morphologically recognized intraductal neoplasms in the mammary ductal tree defined by an increased risk for subsequent invasive carcinomas at or near the site of biopsy detection. However, only 15-45% of untreated DCIS cases progress to invasive cancer, so understanding mechanisms that prevent progression is key to avoid overtreatment and provides a basis for alternative therapies and prevention. This study was designed to characterize the tumor microenvironment and molecular profile of high-risk DCIS that grew to a large size but remained as DCIS.

Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer.

Unlabelled: Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers.

Systematic annotation of orphan RNAs reveals blood-accessible molecular barcodes of cancer identity and cancer-emergent oncogenic drivers.

From extrachromosomal DNA to neo-peptides, the broad reprogramming of the cancer genome leads to the emergence of molecules that are specific to the cancer state. We recently described orphan non-coding RNAs (oncRNAs) as a class of cancer-specific small RNAs with the potential to play functional roles in breast cancer progression. Here, we report a systematic and comprehensive search to identify, annotate, and characterize cancer-emergent oncRNAs across 32 tumor types.

Association of antibiotic exposure with residual cancer burden in HER2-negative early stage breast cancer.

Antibiotic exposure during immunotherapy (IO) has been shown to negatively affect clinical outcomes in various cancer types. The aim of this study was to evaluate whether antibiotic exposure in patients with high-risk early-stage HER2-negative breast cancer (BC) undergoing treatment with neoadjuvant pembrolizumab impacted residual cancer burden (RCB) and pathologic complete response (pCR) in the pembrolizumab-4 arm of the ISPY-2 clinical trial. Patients received pembrolizumab for four cycles concurrently with weekly paclitaxel for 12 weeks, followed by four cycles of doxorubicin plus cyclophosphamide every 2 or 3 weeks.

Differences in the mechanical properties of intestinal tissue based on preservation freezing duration and temperature.

In this study, tissue samples were stress tested to determine if freezing duration and temperature alter their mechanical properties. Tissue samples taken from the small intestine of pigs were assigned to 5 groups: fresh tissue, -28.9 °C for 7 days, -62.

Duration of Endocrine Treatment for DCIS impacts second events: Insights from a large cohort of cases at two academic medical centers.

Ductal carcinoma in situ (DCIS) incidence has risen rapidly with the introduction of screening mammography, yet it is unclear who benefits from both the amount and type of adjuvant treatment (radiation therapy, (RT), endocrine therapy (ET)) versus what constitutes over-treatment. Our goal was to identify the effects of adjuvant RT, or ET+/- RT versus breast conservation surgery (BCS) alone in a large multi-center registry of retrospective DCIS cases (N = 1,916) with median follow up of 8.2 years.

Race, Gene Expression Signatures, and Clinical Outcomes of Patients With High-Risk Early Breast Cancer.

Importance: There has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes.

Objective: To evaluate associations between clinical trial end points, namely pathologic complete response (pCR) and distant recurrence-free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race.

Design, Setting, And Participants: This retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer.

Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation.

The salt-inducible kinases (SIK) 1-3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study of the optimal SIK isoform selectivity profile for suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy for developing potent SIK inhibitors that are highly selective against other kinases by engaging two differentiating features of the SIK catalytic site.

B-cells and regulatory T-cells in the microenvironment of HER2+ breast cancer are associated with decreased survival: a real-world analysis of women with HER2+ metastatic breast cancer.

Background: Despite major improvements in treatment of HER2-positive metastatic breast cancer (MBC), only few patients achieve complete remission and remain progression free for a prolonged time. The tumor immune microenvironment plays an important role in the response to treatment in HER2-positive breast cancer and could contain valuable prognostic information. Detailed information on the cancer-immune cell interactions in HER2-positive MBC is however still lacking.

Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes.

Introduction: Drug resistance is a major obstacle in cancer treatment and can involve a variety of different factors. Identifying effective therapies for drug resistant tumors is integral for improving patient outcomes.

Methods: In this study, we applied a computational drug repositioning approach to identify potential agents to sensitize primary drug resistant breast cancers.

Therapist Feedback and Implications on Adoption of an Artificial Intelligence-Based Co-Facilitator for Online Cancer Support Groups: Mixed Methods Single-Arm Usability Study.

Background: The recent onset of the COVID-19 pandemic and the social distancing requirement have created an increased demand for virtual support programs. Advances in artificial intelligence (AI) may offer novel solutions to management challenges such as the lack of emotional connections within virtual group interventions. Using typed text from online support groups, AI can help identify the potential risk of mental health concerns, alert group facilitator(s), and automatically recommend tailored resources while monitoring patient outcomes.

Development and testing of a polygenic risk score for breast cancer aggressiveness.

Aggressive breast cancers portend a poor prognosis, but current polygenic risk scores (PRSs) for breast cancer do not reliably predict aggressive cancers. Aggressiveness can be effectively recapitulated using tumor gene expression profiling. Thus, we sought to develop a PRS for the risk of recurrence score weighted on proliferation (ROR-P), an established prognostic signature.