Socioecologic Factors and Racial Differences in Breast Cancer Multigene Prognostic Scores in US Women.

Importance: Disproportionately aggressive tumor biology among non-Hispanic Black women with early-stage, estrogen receptor (ER)-positive breast cancer contributes to racial disparities in breast cancer mortality. It is unclear whether socioecologic factors underlie racial differences in breast tumor biology. Objective: To examine individual-level (insurance status) and contextual (area-level socioeconomic position and rural or urban residence) factors as possible mediators of racial and ethnic differences in the prevalence of ER-positive breast tumors with aggressive biology, as indicated by a high-risk gene expression profile. Design, Setting, and Participants: This retrospective cohort study included women 18 years or older diagnosed with stage I to II, ER-positive breast cancer between January 1, 2007, and December 31, 2015. All data analyses were conducted between December 2022 and April 2023. Main Outcomes and Measures: The primary outcome was the likelihood of a high-risk recurrence score (RS) (≥26) on the Oncotype DX 21-gene breast tumor prognostic genomic biomarker. Results: Among 69 139 women (mean [SD] age, 57.7 [10.5] years; 6310 Hispanic [9.1%], 274 non-Hispanic American Indian and Alaskan Native [0.4%], 6017 non-Hispanic Asian and Pacific Islander [8.7%], 5380 non-Hispanic Black [7.8%], and 51 158 non-Hispanic White [74.0%]) included in our analysis, non-Hispanic Black (odds ratio [OR], 1.33; 95% CI, 1.23-1.43) and non-Hispanic American Indian and Alaska Native women (OR, 1.38; 95% CI, 1.01-1.86) had greater likelihood of a high-risk RS compared with non-Hispanic White women. There were no significant differences among other racial and ethnic groups. Compared with non-Hispanic White patients, there were greater odds of a high-risk RS for non-Hispanic Black women residing in urban areas (OR, 1.35; 95% CI, 1.24-1.46), but not among rural residents (OR, 1.05; 95% CI, 0.77-1.41). Mediation analysis demonstrated that lack of insurance, county-level disadvantage, and urban vs rural residence partially explained the greater odds of a high-risk RS among non-Hispanic Black women (proportion mediated, 17%; P < .001). Conclusions and Relevance: The findings of this cohort study suggest that the consequences of structural racism extend beyond inequities in health care to drive disparities in breast cancer outcome. Additional research is needed with more comprehensive social and environmental measures to better understand the influence of social determinants on aggressive ER-positive tumor biology among racial and ethnic minoritized women from disadvantaged and historically marginalized communities.

Are We the Problem? A Call to Action for Addressing Institutional Challenges to Engaging Community Partners in Research.

Community-engaged research (CEnR) is a potent tool for addressing health inequities and fostering equitable relationships among communities, researchers, and institutions. CEnR involves collaboration throughout the research process, demonstrating improvements in study recruitment and retention, intervention efficacy, program sustainability, capacity building among partners, and enhanced cultural relevance. Despite the increasing demand for CEnR, institutional policies, particularly human participation protection training (HPP), lag behind, creating institutional barriers to community partnerships. Here, we highlight challenges encountered in our ongoing study, Fostering Opportunities in Research through Messaging and Education (FOR ME), focused on promoting shared decision-making around clinical trial participation among Black women diagnosed with breast cancer. Grounded in CEnR methods, FOR ME has a partnership with a community-based organization (CBO) that addresses the needs of Black women with breast cancer. Our CBO partner attempted to obtain HPP training, which was administratively burdensome and time-consuming. As CEnR becomes more prevalent, academic and research institutions, along with researchers, are faced with a call to action to become more responsive to community partner needs. Accordingly, we present a guide to HPP training for community partners, addressing institutional barriers to community partner participation in research. This guide outlines multiple HPP training pathways for community partners, aiming to minimize institutional barriers and enhance their engagement in research with academic partners.

Reduction in Breast Cancer Death With Adjuvant Chemotherapy Among US Women According to Race, Ethnicity, and the 21-Gene Recurrence Score.

BACKGROUND: We previously showed the 21-gene breast recurrence score (RS) has lower prognostic accuracy for non-Hispanic Black (NHB) compared with non-Hispanic White (NHW) women with estrogen receptor (ER)-positive/HER2-negative breast cancer. The purpose of this study was to determine the clinical validity of the RS for predicting chemotherapy benefit as recommended in the current NCCN Guidelines for Breast Cancer among women from diverse racial/ethnic groups. METHODS: Using the SEER Oncotype database, we estimated propensity score-weighted hazard ratios (HRs) and 95% confidence intervals for breast cancer death with chemotherapy for women with ER-positive/HER2-negative, AJCC stages I-II, axillary node-negative, invasive breast cancer according to race/ethnicity. RESULTS: We included 6,033 (8.2%) Asian/Pacific Islander (API), 5,697 (7.8%) NHB, 6,688 (9.1%) Hispanic, and 54,945 (74.9%) NHW women. Breast cancer death was reduced with chemotherapy for NHB (HR, 0.48, 95% CI, 0.28-0.81), Hispanic (HR, 0.48; 95% CI, 0.25-0.94), and NHW (HR, 0.80; 95% CI, 0.65-0.99) women with an RS of 26 to 100. There was a nonsignificant reduction for API women (HR, 0.59; 95% CI, 0.28-1.24). For women with an RS of 11 to 25, there was no reduction in death for any racial/ethnic group. Among women aged ≤50 years, the reduction in breast cancer death with chemotherapy differed according to race (NHB: HR, 0.37 [95% CI, 0.20-0.67]; NHW: HR, 0.56 [95% CI, 0.44-0.74]; Pinteraction for chemotherapy * race <.0499). An exploratory subgroup analysis found that young NHB women may benefit from chemotherapy at a lower RS cutoff than other women. CONCLUSIONS: The RS was clinically validated as a predictive biomarker for NHB, Hispanic, and NHW women with ER-positive, axillary node-negative breast cancer, but it may underestimate the benefit of chemotherapy for young NHB women. If this finding is confirmed, the RS cutoff for recommending adjuvant chemotherapy for young NHB women with ER-positive, axillary node-negative breast cancer may need to be lower than for other women.

Multiplex Imaging Reveals Novel Subcellular, Microenvironmental, and Racial Patterns of MRTFA/B Activation in Invasive Breast Cancers and Metastases.

Breast cancer progression and metastasis involve the action of multiple transcription factors in tumors and in the cells of the tumor microenvironment (TME) and understanding how these transcription factors are coordinated can guide novel therapeutic strategies. Myocardin related transcription factors A and B (MRTFA/B) are two related transcription factors that redundantly control cancer cell invasion and metastasis in mouse models of breast cancer, but their roles in human cancer are incompletely understood. Here, we used a combination of multiplexed immunofluorescence and bioinformatics analyses to show that MRTFA/B are concurrently activated in tumor cells, but they show distinct patterns of expression across different histological subtypes and in the TME. Importantly, MRTFA expression was elevated in metastatic tumors of African American patients, who disproportionately die from breast cancer. Interestingly, in contrast to publicly available mRNA expression data, MRTFA was similarly expressed across estrogen receptor (ER) positive and negative breast tumors, while MRTFB expression was highest in ER+ breast tumors. Furthermore, MRTFA was specifically expressed in the perivascular antigen presenting cells (APCs) and its expression correlated with the expression of the immune checkpoint protein V-set immunoregulatory receptor (VSIR). These results provide unique insights into how MRTFA and MRTFB can promote metastasis in human cancer, into the racial disparities of their expression patterns, and their function within the complex breast cancer TME.

Risk of contralateral breast cancer among Asian/Pacific Islander women in the United States.

PURPOSE: While breast cancer studies often aggregate Asian/Pacific Islander (API) women, as a single group or exclude them, this population is heterogeneous in terms of genetic background, environmental exposures, and health-related behaviors, potentially resulting in different cancer outcomes. Our purpose was to evaluate risks of contralateral breast cancer (CBC) among subgroups of API women with breast cancer. METHODS: We conducted a retrospective cohort study of women ages 18 + years diagnosed with stage I-III breast cancer between 2000 and 2016 in the Surveillance, Epidemiology and End Results registries. API subgroups included Chinese, Japanese, Filipina, Native Hawaiian, Korean, Vietnamese, Indian/Pakistani, and other API women. Asynchronous CBC was defined as breast cancer diagnosed in the opposite breast 12 + months after first primary unilateral breast cancer. Multivariable-adjusted subdistribution hazard ratios (SHR) and 95% confidence intervals (CI) were estimated and stratified by API subgroups. RESULTS: From a cohort of 44,362 API women with breast cancer, 25% were Filipina, 18% were Chinese, 14% were Japanese, and 8% were Indian/Pakistani. API women as an aggregate group had increased risk of CBC (SHR 1.15, 95% CI 1.08-1.22) compared to NHW women, among whom Chinese (SHR 1.23, 95% CI 1.08-1.40), Filipina (SHR 1.37, 95% CI 1.23-1.52), and Native Hawaiian (SHR 1.69, 95% CI 1.37-2.08) women had greater risks. CONCLUSION: Aggregating or excluding API patients from breast cancer studies ignores their heterogeneous health outcomes. To advance cancer health equity among API women, future research should examine inequities within the API population to design interventions that can adequately address their unique differences.

Identification of metabolic pathways contributing to ER+ breast cancer disparities using a machine-learning pipeline.

African American (AA) women in the United States have a 40% higher breast cancer mortality rate than Non-Hispanic White (NHW) women. The survival disparity is particularly striking among (estrogen receptor positive) ER+ breast cancer cases. The purpose of this study is to examine whether there are racial differences in metabolic pathways typically activated in patients with ER+ breast cancer. We collected pretreatment plasma from AA and NHW ER+ breast cancer cases (AA n = 48, NHW n = 54) and cancer-free controls (AA n = 100, NHW n = 48) to conduct an untargeted metabolomics analysis using gas chromatography mass spectrometry (GC-MS) to identify metabolites that may be altered in the different racial groups. Unpaired t-test combined with multiple feature selection and prediction models were employed to identify race-specific altered metabolic signatures. This was followed by the identification of altered metabolic pathways with a focus in AA patients with breast cancer. The clinical relevance of the identified pathways was further examined in PanCancer Atlas breast cancer data set from The Cancer Genome Atlas Program (TCGA). We identified differential metabolic signatures between NHW and AA patients. In AA patients, we observed decreased circulating levels of amino acids compared to healthy controls, while fatty acids were significantly higher in NHW patients. By mapping these metabolites to potential epigenetic regulatory mechanisms, this study identified significant associations with regulators of metabolism such as methionine adenosyltransferase 1A (MAT1A), DNA Methyltransferases and Histone methyltransferases for AA individuals, and Fatty acid Synthase (FASN) and Monoacylglycerol lipase (MGL) for NHW individuals. Specific gene Negative Elongation Factor Complex E (NELFE) with histone methyltransferase activity, was associated with poor survival exclusively for AA individuals. We employed a comprehensive and novel approach that integrates multiple machine learning and statistical methods, coupled with human functional pathway analyses. The metabolic profile of plasma samples identified may help elucidate underlying molecular drivers of disproportionately aggressive ER+ tumor biology in AA women. It may ultimately lead to the identification of novel therapeutic targets. To our knowledge, this is a novel finding that describes a link between metabolic alterations and epigenetic regulation in AA breast cancer and underscores the need for detailed investigations into the biological underpinnings of breast cancer health disparities.

Association between adverse childhood experiences and later-life allostatic load in UK Biobank female participants.

BACKGROUND: Adverse childhood experiences during key developmental periods have been shown to impact long-term health outcomes. Adverse childhood experiences may include psychological, physical, or sexual abuse; neglect; or socioeconomic factors. Adverse childhood experiences are linked with an increase in poor health behavior such as smoking and alcohol consumption, and may also influence epigenetic changes, inflammatory response, metabolic changes, and allostatic load. OBJECTIVE: We sought to explore associations between adverse childhood experiences and allostatic load in adult female participants in the UK Biobank. DESIGN: The UK Biobank is a multisite cohort study established to capture lifestyle, environment, exposure, health history, and genotype data on individuals in the United Kingdom. METHODS: Adverse childhood experiences were assessed from the Childhood Trauma Screener, which measures abuse and neglect across five items. Biological measures at enrollment were used to construct allostatic load, including measures of metabolic, inflammatory, and cardiovascular function. Females with a cancer diagnosis prior to enrollment were removed as it may influence allostatic load. Poisson regression models were used to assess the association between adverse childhood experiences and allostatic load, accounting for a priori confounders. RESULTS: A total of 33,466 females with complete data were analyzed, with a median age at enrollment of 54 (range = 40-70) years. Among the study sample, the mean allostatic load ranged from 1.85 in those who reported no adverse childhood experiences to 2.45 in those with all adverse childhood experiences reported. In multivariable analysis, there was a 4% increase in average allostatic load among females for every additional adverse childhood experience reported (incidence rate ratio = 1.04, 95% confidence interval = 1.03-1.05). Similar results were observed when assessing individual adverse childhood experience components. CONCLUSION: This analysis supports a growing body of evidence suggesting that increased exposure to early life abuse or neglect is associated with increased allostatic load in females.

Association of Social Determinants and Tumor Biology With Racial Disparity in Survival From Early-Stage, Hormone-Dependent Breast Cancer.

Importance: Black women with hormone receptor-positive breast cancer experience the greatest racial disparity in survival of all breast cancer subtypes. The relative contributions of social determinants of health and tumor biology to this disparity are uncertain. Objective: To determine the proportion of the Black-White disparity in breast cancer survival from estrogen receptor (ER)-positive, axillary node-negative breast cancer that is associated with adverse social determinants and high-risk tumor biology. Design, Setting, and Participants: A retrospective mediation analysis of factors associated with the racial disparity in breast cancer death for cases diagnosed between 2004 and 2015 with follow-up through 2016 was carried out using the Surveillance, Epidemiology, and End Results (SEER) Oncotype registry. The study included women in the SEER-18 registry who were aged 18 years or older at diagnosis of a first primary invasive breast cancer tumor that was axillary node-negative and ER-positive, who were Black (Black), non-Hispanic White (White), and for whom the 21-gene breast recurrence score was available. Data analysis took place between March 4, 2021, and November 15, 2022. Exposures: Census tract socioeconomic disadvantage, insurance status, tumor characteristics including the recurrence score, and treatment variables. Main Outcomes and Measures: Death due to breast cancer. Results: The analysis with 60 137 women (mean [IQR] age 58.1 [50-66] years) included 5648 (9.4%) Black women and 54 489 (90.6%) White women. With a median (IQR) follow-up time of 56 (32-86) months, the age-adjusted hazard ratio (HR) for breast cancer death among Black compared with White women was 1.82 (95% CI, 1.51-2.20). Neighborhood disadvantage and insurance status together mediated 19% of the disparity (mediated HR, 1.62; 95% CI, 1.31-2.00; P < .001) and tumor biological characteristics mediated 20% (mediated HR, 1.56; 95% CI, 1.28-1.90; P < .001). A fully adjusted model that included all covariates accounted for 44% of the racial disparity (mediated HR, 1.38; 95% CI, 1.11-1.71; P < .001). Neighborhood disadvantage mediated 8% of the racial difference in the probability of a high-risk recurrence score (P = .02). Conclusions and Relevance: In this study, racial differences in social determinants of health and indicators of aggressive tumor biology including a genomic biomarker were equally associated with the survival disparity in early-stage, ER-positive breast cancer among US women. Future research should examine more comprehensive measures of socioecological disadvantage, molecular mechanisms underlying aggressive tumor biology among Black women, and the role of ancestry-related genetic variants.

TrkA expression directs the anti-neoplastic activity of MLK3 inhibitors in triple-negative breast cancer.

Mixed Lineage Kinase 3 (MLK3) is a viable target for neoplastic diseases; however, it is unclear whether its activators or inhibitors can act as anti-neoplastic agents. We reported that the MLK3 kinase activity was higher in triple-negative (TNBC) than in hormone receptor-positive human breast tumors, where estrogen inhibited MLK3 kinase activity and provided a survival advantage to ER+ breast cancer cells. Herein, we show that in TNBC, the higher MLK3 kinase activity paradoxically promotes cancer cell survival. Knockdown of MLK3 or MLK3 inhibitors, CEP-1347 and URMC-099, attenuated tumorigenesis of TNBC cell line and Patient-Derived (PDX) xenografts. The MLK3 kinase inhibitors decreased both the expression and activation of MLK3, PAK1, and NF-kB protein and caused cell death in TNBC breast xenografts. RNA-seq analysis identified several genes downregulated by MLK3 inhibition, and the NGF/TrkA MAPK pathway was significantly enriched in tumors sensitive to growth inhibition by MLK3 inhibitors. The TNBC cell line unresponsive to kinase inhibitor had substantially lower TrkA, and overexpression of TrkA restored the sensitivity to MLK3 inhibition. These results suggest that the functions of MLK3 in breast cancer cells depend on downstream targets in TNBC tumors expressing TrkA, and MLK3 kinase inhibition may provide a novel targeted therapy.

Mixed lineage kinase 3 and CD70 cooperation sensitize trastuzumab-resistant HER2+ breast cancer by ceramide-loaded nanoparticles.

Trastuzumab is the first-line therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but often patients develop acquired resistance. Although other agents are in clinical use to treat trastuzumab-resistant (TR) breast cancer; still, the patients develop recurrent metastatic disease. One of the primary mechanisms of acquired resistance is the shedding/loss of the HER2 extracellular domain, where trastuzumab binds. We envisioned any new agent acting downstream of the HER2 should overcome trastuzumab resistance. The mixed lineage kinase 3 (MLK3) activation by trastuzumab is necessary for promoting cell death in HER2+ breast cancer. We designed nanoparticles loaded with MLK3 agonist ceramide (PPP-CNP) and tested their efficacy in sensitizing TR cell lines, patient-derived organoids, and patient-derived xenograft (PDX). The PPP-CNP activated MLK3, its downstream JNK kinase activity, and down-regulated AKT pathway signaling in TR cell lines and PDX. The activation of MLK3 and down-regulation of AKT signaling by PPP-CNP induced cell death and inhibited cellular proliferation in TR cells and PDX. The apoptosis in TR cells was dependent on increased CD70 protein expression and caspase-9 and caspase-3 activities by PPP-CNP. The PPP-CNP treatment alike increased the expression of CD70, CD27, cleaved caspase-9, and caspase-3 with a concurrent tumor burden reduction of TR PDX. Moreover, the expressions of CD70 and ceramide levels were lower in TR than sensitive HER2+ human breast tumors. Our in vitro and preclinical animal models suggest that activating the MLK3-CD70 axis by the PPP-CNP could sensitize/overcome trastuzumab resistance in HER2+ breast cancer.

Healthcare Predictors of Information Dissemination About Genetic Risks.

OBJECTIVES: Despite the benefits of genetic counseling and testing (GCT), utilization is particularly low among African American (AA) women who exhibit breast cancer features that are common in BRCA-associated cancer. Underutilization is especially problematic for AA women who are more likely to die from breast cancer than women from any other race or ethnicity. Due to medical mistrust, fear, and stigma that can be associated with genetic services among racial/ethnic minorities, reliance on trusted social networks may be an impactful strategy to increase dissemination of knowledge about hereditary cancer risk. Informed by the social cognitive theory, the purpose of this study is to determine: 1) which AA patients diagnosed with breast cancer and with identified hereditary risk are sharing information about hereditary risk with their networks; 2) the nature of the information dissemination; and 3) if personal GCT experiences is associated with dissemination of information about hereditary risk. METHODS: Among consented participants (n = 100) that completed an interview administered using a 202-item questionnaire consisting of open- and closed-ended questions, 62 patients were identified to be at higher risk for breast cancer. Descriptive statistics, bivariable chi-square, Pearson's exact tests, and regression analyses were conducted to examine differences in characteristics between high-risk participants who disseminated hereditary risk information and participants who did not. RESULTS: Among high-risk participants, 25 (40%) indicated they had disseminated information about hereditary risk to at least one member in their family/friend network and 37 (60%) had not. Receipt of both provider recommendations and receipt of GCT services was associated with greater odds of disseminating information about hereditary risk with networks, OR = 4.53, 95%CI [1.33, 15.50], p = .02. CONCLUSION: Interventions that increase self-efficacy gained through additional personalized knowledge and experience gained through provider recommendations and by undergoing GCT may facilitate information dissemination among social/familial networks.

Pilot study of a culturally sensitive intervention to promote genetic counseling for breast cancer risk.

BACKGROUND: Despite the benefits of genetic counseling and testing, uptake of cancer genetic services is generally low and Black/African American (Black) women are substantially less likely to receive genetic services than non-Hispanic White women. Our team developed a culturally sensitive, narrative decision aid video to promote uptake of genetic counseling among Black women at risk for a hereditary breast cancer syndrome that can be incorporated in conjunction with population-based cancer risk assessment in a clinical setting. We report here a pilot study to demonstrate changes in intention to access genetic counseling and intervention satisfaction. METHODS: Black women who were personally unaffected by breast cancer and were recommended for genetic counseling based on family history screening in a mammography center were recruited at the time of the mammogram. A prospective, pre-post survey study design, guided by theoretical constructs, was used to evaluate baseline and immediate post-intervention psychosocial factors, including intention to participate in genetic counseling and intervention satisfaction. RESULTS: Pilot recruitment goals were met (n = 30). Pre-intervention, 50% of participants indicated that they were extremely likely to make a genetic counseling appointment, compared with 70% post-intervention (p = 0.05). After watching the intervention, 50% of participants indicated that the video changed their mind regarding genetic counseling. CONCLUSIONS: This study demonstrated cultural satisfaction with a decision aid intervention designed to motivate Black women with hereditary breast cancer risk to attend a genetic counseling appointment. Our study showed that intention may be a specific and key construct to target in interventions designed to support decision-making about genetic services. Study results informed the design of a subsequent large scale, randomized implementation study. TRIAL REGISTRATION: Trial registration: Clinicaltrials.gov NCT04082117 . Registered September 9, 2019. Retrospectively registered.

Physical functioning, frailty and risks of locally-advanced breast cancer among older women.

OBJECTIVE: Women with multiple comorbidities have competing health needs that may delay screening for early detection of breast cancer. Our objective was to determine associations between physical functioning and frailty with risk of locally-advanced breast cancer (BC). METHODS: We conducted a retrospective cohort study of women 65 years and older diagnosed with first primary stage I-III BC using the Surveillance, Epidemiology and End Results Medicare Health Outcome Survey Data Resource. Physical health-related quality of life was measured using Veterans RAND 12 Item Health Survey scales within two years before diagnosis; frailty was determined by calculating deficit-accumulation frailty index (DAFI) scores. Multivariable modified Poisson regression models were used to estimate rate ratios (RR) and 95% confidence intervals (CI) for risk of locally-advanced (stage III) versus early-stage (I-II) BC. RESULTS: Among 2411 women with a median age of 75 years at BC diagnosis, 2189 (91%) were diagnosed with incident stage I-II BC and 222 (9%) were diagnosed at stage III. Compared to women with early-stage disease, women with locally-advanced BC had lower physical component scores (37.8 vs. 41.4) and more classified as pre-frail or frail (55% vs. 50%). In multivariable models, frailty was not associated with increased risk of locally-advanced disease. However, worse physical function subscale scores (lowest vs. upper quartile; RR = 1.56, 95% CI 1.04-2.34) were associated with risk of locally-advanced BC. CONCLUSIONS: Breast cancer screening among non-frail older women should be personalized to include women with limited physical functioning if the benefits of screening and early detection outweigh the potential harms.

Impact of socioeconomic status and rurality on cancer-specific survival among women with de novo metastatic breast cancer by race/ethnicity.

PURPOSE: There are approximately 150,000 women living with metastatic breast cancer (mBC) in the United States. Disparities in de novo mBC incidence and mortality exist across race/ethnicity, socioeconomic status (SES), and rurality. However, how SES and rurality independently impact mBC outcomes across different racial/ethnic groups is not fully understood. The purpose of this study was to determine the impact of SES and rurality on cancer-specific mortality among women with mBC by race/ethnicity. METHODS: We conducted a large, population-based retrospective cohort study in women aged 18 + years diagnosed with de novo mBC using the Surveillance, Epidemiology and End Results Census Tract-level SES and Rurality Database (2000-2015). Associations between SES/rurality and cancer-specific mortality were determined using Fine and Gray regression models. Subdistribution hazard ratios (SHR) and 95% confidence intervals (CI) by race/ethnicity and hormone receptor (HR) status were calculated. RESULTS: A cohort of 33,976 women were included with the majority being White (67%), 17% Black, 0.4% American Indian/Alaskan Native, 6% Asian/Pacific Islander, and 10% Latina/Hispanic. We observed the greatest increased risk of BC mortality among Black women with HR-negative mBC residing in neighborhoods with lower SES (lowest versus highest quintile: SHR 1.38, 95% CI 1.00-1.90) and in rural areas compared to urban areas (SHR 1.27, 95% CI 1.01-1.59). CONCLUSION: Overall, BC-specific survival among women with de novo mBC differs by race/ethnicity, with the greatest adverse impacts of SES and rurality affecting Black women with HR-negative disease.

Understanding Racial and Ethnic Inequities in Uptake and Outcomes Following Multigene Prognostic Testing in Early Breast Cancer: The Promise of Real-World Data.

In the past decades, multigene prognostic testing, such as Oncotype DX (ODX), has been increasingly used to inform treatment decisions for patients with early-stage breast cancer. This advance in precision oncology has increased existing concerns about differential access to genomic testing across racial and ethnic groups. The investigation by Moore and colleagues, analyzing real-world data from the National Cancer Database, shows that patients of color with breast cancer were less likely to receive ODX testing and Black patients were more likely to have a high risk Recurrence Score (RS) compared with White patients. This study emphasizes that the appropriate adoption of ODX testing is critical to promote equitable cancer care for patients with breast cancer. The reported associations on overall survival across specific racial and ethnic groups provided here give additional insight to the known associations between the ODX RS and outcomes of distant recurrence and cancer-specific mortality. Analyses of contemporary, real-world data from diverse populations with long-term follow-up should continue to keep pace with the expansion of precision breast cancer care to better understand and mitigate potentially widening inequities in genomic testing. See related article by Moore et al., p. 821.

Impact of time to distant recurrence on breast cancer-specific mortality in hormone receptor-positive breast cancer.

Women with hormone receptor (HR)-positive early-stage breast cancer (BC) have five-year survival rates of > 90% but remain at serious risk for developing distant metastases beyond five years from diagnosis. This retrospective cohort study used data from the Surveillance, Epidemiology, and End Results (SEER) registries to examine associations between distant recurrence-free interval (DRFI) and risk of BC-specific mortality following distant relapse. The analysis includes 1,057 women with second primary stage IV BC who were initially diagnosed with AJCC stages I-III HR-positive BC between1990 and 2016. Overall, 65% of women had a preceding DRFI of ≥ 5 years. Five-year BC-specific survival following development of distant recurrence was 52% for women with DRFI ≥ 5 years compared to 31% in women with DRFI of < 5 years. In multivariable analyses, risks of cancer-specific mortality following distant recurrence were lower in women with DRFI of 5 years or more (subdistribution hazard ratio = 0.72, 95% CI 0.58-0.89, p = 0.002). The results of this study may inform patient-clinician discussions surrounding prognosis and treatment selection among HR-positive patients who develop a distant recurrence of disease.

The association between physical health-related quality of life, physical functioning, and risk of contralateral breast cancer among older women.

BACKGROUND: Physical limitations prior to cancer diagnosis may lead to suboptimal health outcomes. Our objective was to evaluate the impacts of poor physical health-related quality of life (HRQOL) and physical functioning (PF) on the risk of contralateral breast cancer (CBC). METHODS: We performed a nested case-control study of women with invasive unilateral breast cancer (UBC) who did not receive prophylactic contralateral mastectomy using the Surveillance, Epidemiology and End Results Medicare Health Outcomes Survey data resource. Among 2938 women aged ≥ 65 years diagnosed with first stage I-III UBC between 1997 and 2011, we identified 100 subsequent CBC cases and 915 matched controls without CBC using incidence density sampling without replacement. Pre-diagnosis physical HRQOL and PF were determined using Medical Outcomes Trust Short Form-36 (SF-36)/Veterans Rand 12-Item Health Survey (VR-12) responses within 2 years prior to first UBC diagnosis. We estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression models. RESULTS: Cases and controls were similar with respect to comorbidities, stage, surgery, and radiation treatments, but differed by hormone receptor status (ER/PR-negative, 23% and 11%, respectively) of first UBC. Cases had modestly lower mean pre-diagnosis physical HRQOL (- 1.8) and PF (- 2.2) scores. In multivariable models, we observed an increased CBC risk associated with low physical HRQOL (lowest vs. highest quartile, OR = 1.8; 95% CI 0.8-4.3), but CIs included 1.0. Low PF was associated with a 2.7-fold (95% CI 1.1-6.7) increased CBC risk. CONCLUSIONS: Findings indicate that low physical HRQOL, specifically poor PF, is associated with CBC risk. Efforts to understand and minimize declines in PF post-breast cancer are well motivated.