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Background: Young women treated for breast cancer with cytotoxic therapies are at risk for clonal hematopoiesis of indeterminate potential (CHIP), a condition in which blood cells carrying a somatic mutation associated with hematologic malignancy comprise at least 4% of the total blood system. CHIP has primarily been studied in older patient cohorts with limited clinical phenotyping. Materials and Methods: We performed targeted sequencing on longitudinal blood samples to characterize the clonal hematopoietic landscape of 878 women treated for breast cancer enrolled in the prospective Young Women's Breast Cancer Study. Results: We identified somatic driver mutations in 252 study subjects (28.7%), but only 24 (2.7%) had clones large enough to meet criteria for CHIP. The most commonly mutated genes were DNMT3A and TET2, similar to mutations observed in noncancer cohorts. At 9-year median follow-up, we found no association between the presence of a somatic blood mutation (regardless of clone size) and adverse breast cancer (distant relapse-free survival) or non–breast cancer-related outcomes in this cohort. A subset of paired blood samples obtained over 4 years showed no evidence of mutant clonal expansion, regardless of genotype. Finally, we identified a subset of patients with likely germline mutations in genes known to contribute to inherited cancer risk, such as TP53 and ATM. Conclusions: Our data show that for young women with early-stage breast cancer, CHIP is uncommon after cytotoxic exposure, is unlikely to contribute to adverse outcomes over the decade-long follow-up and may not require additional monitoring if discovered incidentally.

Longitudinal Mutation Analysis in the YWS

Background:Young women treated for breast cancer with cytotoxic therapies are at risk for clonal hematopoiesis of indeterminate potential (CHIP), a condition in which blood cells carrying a somatic mutation associated with hematologic malignancy comprise at least 4% of the total blood system. CHIP has primarily been studied in older patient cohorts with limited clinical phenotyping.Materials and Methods:We performed targeted sequencing on longitudinal blood samples to characterize the clonal hematopoietic landscape of 878 women treated for breast cancer enrolled in the prospective Young Women's Breast Cancer Study.Results:We identified somatic driver mutations in 252 study subjects (28.7%), but only 24 (2.7%) had clones large enough to meet criteria for CHIP. The most commonly mutated genes were DNMT3A and TET2, similar to mutations observed in noncancer cohorts. At 9-year median follow-up, we found no association between the presence of a somatic blood mutation (regardless of clone size) and adverse breast cancer (distant relapse-free survival) or non–breast cancer-related outcomes in this cohort. A subset of paired blood samples obtained over 4 years showed no evidence of mutant clonal expansion, regardless of genotype. Finally, we identified a subset of patients with likely germline mutations in genes known to contribute to inherited cancer risk, such as TP53 and ATM.Conclusions:Our data show that for young women with early-stage breast cancer, CHIP is uncommon after cytotoxic exposure, is unlikely to contribute to adverse outcomes over the decade-long follow-up and may not require additional monitoring if discovered incidentally.

Cohort Characteristics Broken Down by CH (Any VAF)

Supplementary Figure S1. Leukocyte frequencies in breast tissues. Supplementary Figure S2. Genes expressed in T cells. Supplementary Figure S3. Activity status of T cells. Supplementary Figure S4. TCR clonotypes in breast tissues. Supplementary Figure S5. Functional state of T cells. Supplementary Figure S6. Tumor topology. Supplementary Figure S7. Immune-related amplicons in breast cancer.

Supplementary Table S1. List of tissue samples used. Supplementary Table S2. Raw FACS data in each sample. Supplementary Table S3. List of differentially expressed genes. Supplementary Table S4. Results of GSEA analyses. Supplementary Table S5. Gene lists used for functional analyses. Supplementary Table S6. Statistical modeling of ERBB2 and CC co-amplification; and PDL1 amplification. Supplementary Table S7. ERBB2 and 17q12 FISH data. Supplementary Table S8. List of antibodies used.

Kaplan-Meier Curves for Progression-Free Survival and Overall Survival by high TMB {greater than or equal to}7 mutations/Mb and PTEN alterations in Chemotherapy-Treated mTNBC. (A) Progression-free survival and (C) overall survival by tumor mutational burden

Purpose:Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICI). On the basis of immunotherapy response correlates in other cancers, we evaluated whether high tumor mutational burden (TMB) ≥10 nonsynonymous mutations/megabase and PTEN alterations, defined as nonsynonymous mutations or 1 or 2 copy deletions, were associated with clinical benefit to anti-PD-1/L1 therapy in mTNBC.Experimental Design:We identified patients with mTNBC, who consented to targeted DNA sequencing and were treated with ICIs on clinical trials between April 2014 and January 2019 at Dana-Farber Cancer Institute (Boston, MA). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were correlated with tumor genomic features.Results:Sixty-two women received anti-PD-1/L1 inhibitors alone (23%) or combined with targeted therapy (19%) or chemotherapy (58%). High TMB (18%) was associated with significantly longer PFS (12.5 vs. 3.7 months; P = 0.04), while PTEN alterations (29%) were associated with significantly lower ORR (6% vs. 48%; P = 0.01), shorter PFS (2.3 vs. 6.1 months; P = 0.01), and shorter OS (9.7 vs. 20.5 months; P = 0.02). Multivariate analyses confirmed that these associations were independent of performance status, prior lines of therapy, therapy regimen, and visceral metastases. The survival associations were additionally independent of PD-L1 in patients with known PD-L1 and were not found in mTNBC cohorts treated with chemotherapy (n = 90) and non-ICI regimens (n = 169).Conclusions:Among patients with mTNBC treated with anti-PD-1/L1 therapies, high TMB and PTEN alterations were associated with longer and shorter survival, respectively. These observations warrant validation in larger datasets.

Extended methods and results, including e-references

Figure S1. REMARK diagram Figure S2. NanoString Tumor Inflammation Signature by breast cancer intrinsic subtype Figure S3. NanoString individual gene expression changes by cohort Table S1. Pre-treatment immune microenvironment and response to preoperative therapy Table S2. Tissue-based immune biomarkers in patients with pathologic complete response Table S3. References for classification of genes as M1-like or M2-like

Supplemental Figure 1: Study Schema Supplemental Table 1: Tissue Insulin Receptor Staining

Purpose:Hormone receptor–positive/HER2-negative (HR+/HER2−) breast cancer is associated with low levels of stromal tumor-infiltrating lymphocytes (sTIL) and PD-L1, and demonstrates poor responses to checkpoint inhibitor therapy. Evaluating the effect of standard chemotherapy on the immune microenvironment may suggest new opportunities for immunotherapy-based approaches to treating HR+/HER2− breast tumors.Experimental Design:HR+/HER2− breast tumors were analyzed before and after neoadjuvant chemotherapy. sTIL were assessed histologically; CD8+ cells, CD68+ cells, and PD-L1 staining were assessed immunohistochemically; whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed.Results:Ninety-six patients were analyzed from two cohorts (n = 55, Dana-Farber cohort; n = 41, MD Anderson cohort). sTIL, CD8, and PD-L1 on tumor cells were higher in tumors with basal PAM50 intrinsic subtype. Higher levels of tissue-based lymphocyte (sTIL, CD8, PD-L1) and macrophage (CD68) markers, as well as gene expression markers of lymphocyte or macrophage phenotypes (NanoString or CIBERSORT), correlated with favorable response to neoadjuvant chemotherapy, but not with improved distant metastasis-free survival in these cohorts or a large gene expression dataset (N = 302). In paired pre-/postchemotherapy samples, sTIL and CD8+ cells were significantly decreased after treatment, whereas expression analyses (NanoString) demonstrated significant increase of multiple myeloid signatures. Single gene expression implicated increased expression of immunosuppressive (M2-like) macrophage-specific genes after chemotherapy.Conclusions:The immune microenvironment of HR+/HER2− tumors differs according to tumor biology. This cohort of paired pre-/postchemotherapy samples suggests a critical role for immunosuppressive macrophage expansion in residual disease. The role of macrophages in chemoresistance should be explored, and further evaluation of macrophage-targeting therapy is warranted.

Purpose:Exercise after breast cancer diagnosis is associated with lower cancer-specific mortality, but the biological mechanisms through which exercise impacts breast cancer are not fully understood. The Pre-Operative Health and Body (PreHAB) Study was a randomized window-of-opportunity trial designed to test the impact of exercise on Ki-67, gene expression, and other biomarkers in women with breast cancer.Experimental Design:Inactive women with newly diagnosed breast cancer were randomized to an exercise intervention or mind–body control group, and participated in the study between enrollment and surgery (mean 29.3 days). Tumor and serum were collected at baseline and surgery.Results:Forty-nine women were randomized (27 exercise, 22 control). At baseline, mean age was 52.6, body mass index was 30.2 kg/m2, and exercise was 49 minutes/week. Exercise participants significantly increased exercise versus controls (203 vs. 23 minutes/week, P < 0.0001). There were no differences in changes of expression of Ki-67, insulin receptor, and cleaved caspase-3 in exercise participants versus controls. KEGG pathway analysis demonstrated significant upregulation of 18 unique pathways between the baseline biopsy and surgical excision in exercise participants and none in control participants (q < 0.1). Top-ranked pathways included several implicated in immunity and inflammation. Exploratory analysis of tumor immune infiltrates demonstrated a trend toward a decrease in FOXP3+ cells in exercise versus control participants over the intervention period (P = 0.08).Conclusions:A window-of-opportunity exercise intervention did not impact proliferation but led to alterations in gene expression in breast tumors, suggesting that exercise may have a direct effect on breast cancer.See related commentary by Koelwyn and Jones, p. 5179

Supplementary Tables 1-6, Figure 1 from PIK3CA Mutations in In situ and Invasive Breast Carcinomas

The PIK3 signaling pathway has been identified as one of the most important and most frequently mutated pathways in breast cancer. Somatic mutations in the catalytic subunit of PIK3CA have been found in a significant fraction of breast carcinomas, and it has been proposed that mutant PIK3CA plays a role in tumor initiation. However, the majority of primary human tumors analyzed for genetic alterations in PIK3CA have been invasive breast carcinomas and the frequency of PIK3CA mutations in preinvasive lesions has not been explored. To investigate this, we sequenced exons 9 and 20 of PIK3CA in pure ductal carcinoma in situ (DCIS), DCIS adjacent to invasive carcinoma, and invasive ductal breast carcinomas. In a subset of cases, both in situ and invasive areas were analyzed from the same tumor. We found that the frequency of PIK3CA mutations was essentially the same (∼30%) in all three histologic groups. In some cases, in situ and invasive areas of the same tumor were discordant for PIK3CA status, and in two cases in which multiple invasive and adjacent in situ areas within the same tumor were analyzed independently, we detected intratumor heterogeneity for PIK3CA mutations. Our results suggest that mutation of PIK3CA is an early event in breast cancer that is more likely to play a role in breast tumor initiation than in invasive progression, although a potential role for exon 9 mutations in the progression of a subset of DCIS cases cannot be excluded. Cancer Res; 70(14); 5674–8. ©2010 AACR.

Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed in vitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.

This study aimed to assess the relationship between an Interprofessional Collaborative Practice (IPCP) intervention for community-dwelling older adults, Geriatric Outreach and Training with Care! (GOT Care!), and the observed 26% reduction in Emergency Department (ED) visits for the 51 older adult participants. A convergent parallel mixed-methods design was utilized. Demographic data and ED visit data were collected and analyzed using paired-samples t-tests, poisson regression and generalized poisson regression. Stakeholder perspectives were assessed via emailed open-ended surveys and analyzed using content analysis. The quantitative results were transformed into trends that were compared and contrasted with the qualitative themes. The results were consistent with the current literature that IPCP models may have a greater impact on older adults with certain demographic characteristics such as polypharmacy, diabetes and prior ED use, while nursing was identified as an ideal leader for IPCP teams.

Background Postgraduate programs, specialized academic programs, and national health organizations such as the Institute of Medicine (IOM) have identified and begun addressing the gap in knowledge, skills, and factors for successful transition into practice. Purpose The purpose of this study is to examine the relationships and differences among the personal and community resources that promote successful transition for nurse practitioners (NP) who practice in the emergency department (ED) and the skills or procedures they find difficult to perform independently. Methods A descriptive, correlational, comparative study design was conducted using an online survey administered to a convenience sample of NPs with 6 months to 5 years of experience as an NP. Results Findings from this study identified factors associated with successful and unsuccessful transition into practice and help support positive outcomes for health care institutions, ED patients, and NPs practicing in this specialty area. Implications for practice Support in transition recognizes recommendations set by health care organizations in promoting professional development, safe clinical practice, job satisfaction, and retention. Further study will provide clarity in financial gains and improved patient health outcomes during a time in which complex disease processes and provider shortages continue to weigh heavily on society.

Background Hemorrhagic strokes have not declined in the United States despite a decline worldwide. Purpose To identify hemorrhagic stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs), other medications associated with increased risk for hemorrhagic stroke, and diabetes, cardiovascular disease, gender, and age. Methods A post hoc design was used to examine predictors of hemorrhagic stroke for adults of age 65 years and older from the Food and Drug Administration Adverse Events Reporting System database. The initial sample consisted of all cases reported during the third quarter of 2016 and the second quarter of 2018 with an NSAID as the primary suspect for the adverse drug event (ADE). An additional 397 cases with warfarin as the primary suspect were included in the final sample (N = 3,784) to test for bias from including only NSAID as the primary ADE suspect cases. Extracted data included the primary ADE (hemorrhagic stroke or other ADE), age, gender, primary suspect drug (NSAID or warfarin), and presence of a second NSAID, rivaroxaban, warfarin, clopidogrel, antidepressants (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants), inhaled corticosteroids, diabetes, or cardiovascular medications. Logistic regression was used to predict hemorrhagic stroke. Results Aspirin and warfarin increased the risk for hemorrhagic stroke by 3.458 and 3.059, respectively. Presence of an additional NSAIDs reduced the risk by 48%. Implications for practice Hemorrhagic stroke risk specific to older adults may provide helpful estimates for practitioners as they weigh the risk benefit of prescribing aspirin as an antiplatelet therapy for older adults.

Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified more exhausted T cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.

To compare the impact of exercise and mind-body prehabilitation interventions on changes in quality of life and cancer treatment-related symptoms in women with newly diagnosed breast cancer.The following describes a secondary analysis of a randomized window of opportunity trial (The Pre-Operative Health and Body Study). Forty-nine women were randomized to participate in either an exercise prehabilitation intervention or a mind-body prehabilitation intervention from the time of enrollment to surgery. Participants (N = 47) completed measures of quality of life, anxiety, depression, and stress at the time of enrollment (T1), post-intervention/surgery (T2), and one-month post-surgery (T3). Changes in outcome measures between groups were compared over time using longitudinal models.Mind-body group participants experienced significant improvements in cognitive functioning in comparison to exercise group participants between T1 and T3 (difference in average change: -9.61, p = 0.04, d = 0.31), otherwise, there were no significant differences between groups. Within group comparisons demonstrated that both groups experienced improvements in anxiety (exercise: average change = -1.18, p = 0.03, d = 0.34; mind-body: average change = -1.69, p = 0.006, d = 0.43) and stress (exercise: average change = -2.33, p = 0.04, d = 0.30; mind-body: average change = -2.59, p = 0.05, d = 0.29), while mind-body group participants experienced improvements in insomnia (average change = -10.03, p = 0.04, d = 0.30) and cognitive functioning (average change = 13.16, p = 0.0003, d = 0.67).Both prehabilitation interventions impacted cancer treatment-related symptoms. Further work in larger groups of patients is needed to evaluate the efficacy of prehabilitation interventions on quality of life in women with breast cancer. Pre-operative exercise and mind-body interventions may impact physical and/or psychological effects of cancer diagnosis and treatment in women with breast cancer.ClinicalTrials.gov Identifier: NCT01516190. Registered January 24, 2012.

The aim of the current randomized attention control pilot study was to conduct a preliminary test of a facilitated reminiscence intervention about past physical activity for the effect on increased physical activity and reduced pain in older adults with osteoarthritis. Thirteen older adults were randomized to the facilitated reminiscence or health education group and participated in six individual sessions over 6 weeks. Reminiscence functions, self-reported physical activity, pain intensity, and pain interference with function were measured at baseline and 1 and 3 months postintervention. Facilitated reminiscence did not result in increased physical activity, but instead resulted in increased pain intensity. Content analysis of reminiscence session transcripts indicated most reminiscence was conversational. Benefits from reminiscence included reconnecting with estranged family and distraction from pain. Past physical activities might be helpful to include as part of a program of facilitated integrated reminiscence for individuals with sufficient history of past physical activity. [Res Gerontol Nurs. 2019; 12(4):193–202.]

12089 Background: Metabolic abnormalities may impact breast cancer prognosis, but research has been limited by small samples and assessment of laboratory values at a single time point, often prior to cancer diagnosis and treatment. In a population based cohort, we utilized time-updated laboratory values and adjusted for cancer treatment to assess the association between metabolic risk factors (glucose, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides) and breast cancer survival. Methods: 13,434 women diagnosed with stage I-III breast cancer from 2005-15 at Kaiser Permanente were included. All outpatient fasting glucose, HDL, LDL, and triglyceride values from diagnosis through 2019 or death were extracted from electronic medical records. Lab values were updated a median of 5 times between 1-7 years post-diagnosis. Risk of breast cancer-specific mortality was evaluated with Cox proportional hazards models adjusted for metabolic labs, demographics, body mass index, and diabetes, and then for dyslipidemia and anti-hypertensive medications, tumor characteristics (stage, ER and HER2 receptor status) and cancer treatment (use of chemotherapy, and tamoxifen v. aromatase inhibitors). Results: Mean (SD) age at diagnosis was 62.3 (11.8) years. Over median follow-up of 9 years, 2,876 patients died (1,080 of breast cancer). Patients with low HDL (≤45 vs. >45 mg/dL) had higher breast cancer-specific mortality (HR, 1.87; 95% CI, 1.62-2.16); high levels of glucose, triglycerides, and LDL were not associated. The increased risk associated with low HDL persisted after adjusting for tumor characteristics, cancer treatment, and medications. Conclusions: Low HDL evaluated over time after cancer diagnosis is associated with higher breast cancer mortality independent of cancer treatments and changes in other metabolic risk factors. Cholesterol may play a role in breast cancer due to its role in cell membrane structure, signaling pathways, and steroid hormone synthesis. Future studies should address whether pharmacologic or lifestyle treatment of lipids after breast cancer diagnosis can optimize survival outcomes.[Table: see text]