Declination of Treatment, Racial and Ethnic Disparity, and Overall Survival in US Patients With Breast Cancer.

Importance: Declining treatment negatively affects health outcomes among patients with cancer. Limited research has investigated national trends of and factors associated with treatment declination or its association with overall survival (OS) among patients with breast cancer. Objectives: To examine trends and racial and ethnic disparities in treatment declination and racial and ethnic OS differences stratified by treatment decision in US patients with breast cancer. Design, Setting, and Participants: This retrospective cross-sectional study used data for patients with breast cancer from the 2004 to 2020 National Cancer Database. Four treatment modalities were assessed: chemotherapy, hormone therapy (HT), radiotherapy, and surgery. The chemotherapy cohort included patients with stage I to IV disease. The HT cohort included patients with stage I to IV hormone receptor-positive disease. The radiotherapy and surgery cohorts included patients with stage I to III disease. Data were analyzed from March to November 2023. Exposure: Race and ethnicity and other sociodemographic and clinicopathologic characteristics. Main Outcomes and Measures: Treatment decision, categorized as received or declined, was modeled using logistic regression. OS was modeled using Cox regression. Models were controlled for year of initial diagnosis, age, sex, health insurance, median household income, facility type, Charlson-Deyo comorbidity score, histology, American Joint Committee on Cancer stage, molecular subtype, and tumor grade. Results: The study included 2 837 446 patients (mean [SD] age, 61.6 [13.4] years; 99.1% female), with 1.7% American Indian, Alaska Native, or other patients; 3.5% Asian or Pacific Islander patients; 11.2% Black patients; 5.6% Hispanic patients; and 78.0% White patients. Of 1 296 488 patients who were offered chemotherapy, 124 721 (9.6%) declined; 99 276 of 1 635 916 patients (6.1%) declined radiotherapy; 94 363 of 1 893 339 patients (5.0%) declined HT; and 15 846 of 2 590 963 patients (0.6%) declined surgery. Compared with White patients, American Indian, Alaska Native, or other patients (adjusted odds ratio [AOR], 1.47; 95% CI, 1.26-1.72), Asian or Pacific Islander patients (AOR, 1.29; 95% CI, 1.15-1.44), and Black patients (AOR, 2.01; 95% CI, 1.89-2.14) were more likely to decline surgery; American Indian, Alaska Native, or other patients (AOR, 1.13; 95% CI, 1.05-1.21) and Asian or Pacific Islander patients (AOR, 1.21; 95% CI, 1.16-1.27) were more likely to decline chemotherapy; and Black patients were more likely to decline radiotherapy (AOR, 1.05; 95% CI, 1.02-1.08). Asian or Pacific Islander patients (AOR, 0.81; 95% CI, 0.77-0.85), Black patients (AOR, 0.86; 95% CI, 0.83-0.89), and Hispanic patients (AOR, 0.66; 95% CI, 0.63-0.69) were less likely to decline HT. Furthermore, Black patients who declined chemotherapy had a higher mortality risk than White patients (adjusted hazard ratio [AHR], 1.07; 95% CI, 1.02-1.13), while there were no OS differences between Black and White patients who declined HT (AHR, 1.05; 95% CI, 0.97-1.13) or radiotherapy (AHR, 0.98; 95% CI, 0.92-1.04). Conclusions and Relevance: This cross-sectional study highlights racial and ethnic disparities in treatment declination and OS, suggesting the need for equity-focused interventions, such as patient education on treatment benefits and improved patient-clinician communication and shared decision-making, to reduce disparities and improve patient survival.

Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

A multi-tissue, splicing-based joint transcriptome-wide association study identifies susceptibility genes for breast cancer.

Splicing-based transcriptome-wide association studies (splicing-TWASs) of breast cancer have the potential to identify susceptibility genes. However, existing splicing-TWASs test the association of individual excised introns in breast tissue only and thus have limited power to detect susceptibility genes. In this study, we performed a multi-tissue joint splicing-TWAS that integrated splicing-TWAS signals of multiple excised introns in each gene across 11 tissues that are potentially relevant to breast cancer risk. We utilized summary statistics from a meta-analysis that combined genome-wide association study (GWAS) results of 424,650 women of European ancestry. Splicing-level prediction models were trained in GTEx (v.8) data. We identified 240 genes by the multi-tissue joint splicing-TWAS at the Bonferroni-corrected significance level; in the tissue-specific splicing-TWAS that combined TWAS signals of excised introns in genes in breast tissue only, we identified nine additional significant genes. Of these 249 genes, 88 genes in 62 loci have not been reported by previous TWASs, and 17 genes in seven loci are at least 1 Mb away from published GWAS index variants. By comparing the results of our splicing-TWASs with previous gene-expression-based TWASs that used the same summary statistics and expression prediction models trained in the same reference panel, we found that 110 genes in 70 loci that are identified only by the splicing-TWASs. Our results showed that for many genes, expression quantitative trait loci (eQTL) did not show a significant impact on breast cancer risk, whereas splicing quantitative trait loci (sQTL) showed a strong impact through intron excision events.

Increase in Hypofractionated Radiation Therapy Among Patients with Invasive Breast Cancer or Ductal Carcinoma In Situ: Who is Left Behind?

PURPOSE: We aimed to update the trend of hypofractionated whole-breast irradiation (HF-WBI) use over time in the US and examine factors associated with lack of HF-WBI adoption for patients with early-stage invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) undergoing a lumpectomy. METHODS AND MATERIALS: Among patients who underwent a lumpectomy, we identified 928,034 patients with early-stage IBC and 330,964 patients with DCIS in the 2004 to 2020 National Cancer Database. We defined HF-WBI as 2.5-3.33 Gy/fraction to the breast and conventionally fractionated WBI as 1.8-2.0 Gy/fraction. We evaluated the trend of HF-WBI utilization using a generalized linear model with the log link and binomial distribution. Factors associated with HF-WBI utilization were assessed using multivariable logistic regression in patients diagnosed between 2018 and 2020. RESULTS: Among patients with IBC, HF-WBI use has significantly increased from 0.7% in 2004 to 63.9% in 2020. Similarly, HF-WBI usage among patients with DCIS has also increased significantly from 0.4% in 2004 to 56.6% in 2020. Black patients with IBC were less likely than White patients to receive HF-WBI (adjusted odds ratio [AOR] 0.81; 95% CI, 0.77-0.85). Community cancer programs were less likely to administer HF-WBI to patients with IBC (AOR, 0.80; 95% CI, 0.77-0.84) and to those with DCIS (AOR, 0.87; 95% CI, 0.79-0.96) than academic/research programs. Younger age, positive nodes, larger tumor size, low volume programs, and facility location were also associated with lack of HF-WBI adoption in both patient cohorts. CONCLUSIONS: HF-WBI utilization among postlumpectomy patients has significantly increased from 2004 to 2020 and can finally be considered standard of care in the US. We found substantial disparities in adoption within patient and facility subgroups. Reducing disparities in HF-WBI adoption has the potential to further alleviate health care costs while improving patients' quality of life.

The association of cigarette smoking with DNA methylation and gene expression in human tissue samples.

Cigarette smoking adversely affects many aspects of human health, and epigenetic responses to smoking may reflect mechanisms that mediate or defend against these effects. Prior studies of smoking and DNA methylation (DNAm), typically measured in leukocytes, have identified numerous smoking-associated regions (e.g., AHRR). To identify smoking-associated DNAm features in typically inaccessible tissues, we generated array-based DNAm data for 916 tissue samples from the GTEx (Genotype-Tissue Expression) project representing 9 tissue types (lung, colon, ovary, prostate, blood, breast, testis, kidney, and muscle). We identified 6,350 smoking-associated CpGs in lung tissue (n = 212) and 2,735 in colon tissue (n = 210), most not reported previously. For all 7 other tissue types (sample sizes 38-153), no clear associations were observed (false discovery rate 0.05), but some tissues showed enrichment for smoking-associated CpGs reported previously. For 1,646 loci (in lung) and 22 (in colon), smoking was associated with both DNAm and local gene expression. For loci detected in both lung and colon (e.g., AHRR, CYP1B1, CYP1A1), top CpGs often differed between tissues, but similar clusters of hyper- or hypomethylated CpGs were observed, with hypomethylation at regulatory elements corresponding to increased expression. For lung tissue, 17 hallmark gene sets were enriched for smoking-associated CpGs, including xenobiotic- and cancer-related gene sets. At least four smoking-associated regions in lung were impacted by lung methylation quantitative trait loci (QTLs) that co-localize with genome-wide association study (GWAS) signals for lung function (FEV1/FVC), suggesting epigenetic alterations can mediate the effects of smoking on lung health. Our multi-tissue approach has identified smoking-associated regions in disease-relevant tissues, including effects that are shared across tissue types.

Expression- and splicing-based multi-tissue transcriptome-wide association studies identified multiple genes for breast cancer by estrogen-receptor status.

BACKGROUND: Although several transcriptome-wide association studies (TWASs) have been performed to identify genes associated with overall breast cancer (BC) risk, only a few TWAS have explored the differences in estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer. Additionally, these studies were based on gene expression prediction models trained primarily in breast tissue, and they did not account for alternative splicing of genes. METHODS: In this study, we utilized two approaches to perform multi-tissue TWASs of breast cancer by ER subtype: (1) an expression-based TWAS that combined TWAS signals for each gene across multiple tissues and (2) a splicing-based TWAS that combined TWAS signals of all excised introns for each gene across tissues. To perform this TWAS, we utilized summary statistics for ER + BC from the Breast Cancer Association Consortium (BCAC) and for ER- BC from a meta-analysis of BCAC and the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). RESULTS: In total, we identified 230 genes in 86 loci that were associated with ER + BC and 66 genes in 29 loci that were associated with ER- BC at a Bonferroni threshold of significance. Of these genes, 2 genes associated with ER + BC at the 1q21.1 locus were located at least 1 Mb from published GWAS hits. For several well-studied tumor suppressor genes such as TP53 and CHEK2 which have historically been thought to impact BC risk through rare, penetrant mutations, we discovered that common variants, which modulate gene expression, may additionally contribute to ER + or ER- etiology. CONCLUSIONS: Our study comprehensively examined how differences in common variation contribute to molecular differences between ER + and ER- BC and introduces a novel, splicing-based framework that can be used in future TWAS studies.

Multi-tissue transcriptome-wide association studies identified 235 genes for intrinsic subtypes of breast cancer.

BACKGROUND: Although genome-wide association studies (GWAS) of breast cancer (BC) identified common variants which differ between intrinsic subtypes, genes through which these variants act to impact BC risk have not been fully established. Transcriptome-wide association studies (TWAS) have identified genes associated with overall BC risk, but subtype-specific differences are largely unknown. METHODS: We performed two multi-tissue TWASs for each BC intrinsic subtype including an expression-based approach that collated TWAS signals from expression quantitative trait loci (eQTLs) across multiple tissues and a novel splicing-based approach that collated signals from splicing QTLs (sQTLs) across intron clusters and subsequently across tissues. We utilized summary statistics for five intrinsic subtypes including Luminal A-like, Luminal B-like, Luminal B/HER2-negative-like, HER2-enriched-like, and Triple-negative BC, generated from 106,278 BC cases and 91,477 controls in the Breast Cancer Association Consortium. RESULTS: Overall, we identified 235 genes in 88 loci across were associated with at least one of the five intrinsic subtypes. Most genes were subtype-specific, and many have not been reported in previous TWAS. We discovered common variants that modulate expression of CHEK2 confer increased risk to Luminal-A-like BC, in contrast to the viewpoint that CHEK2 primarily harbors rare, penetrant mutations. Additionally, our splicing-based TWAS provided population-level support for MDM4 splice variants that increased triple-negative BC risk. CONCLUSION: Our comprehensive, multi-tissue TWAS corroborated previous GWAS loci for overall BC risk and intrinsic subtypes, while underscoring how common variation which impacts expression and splicing of genes in multiple tissue types can be used to further elucidate the etiology of BC.

Racial/Ethnic Differences in Pathologic Complete Response to Neoadjuvant Chemotherapy and Survival Among Early-Stage, Erb-B2 Receptor Tyrosine Kinase 2-Low Breast Cancer Patients.

Racial/ethnic differences in pathologic complete response (pCR), and in overall survival (OS) by pCR status, among early-stage, erb-b2 receptor tyrosine kinase 2 (ERBB2)-low breast cancer patients after neoadjuvant chemotherapy (NACT) are unknown. Data were from the 2010-2020 National Cancer Database that included Asian/Pacific Islander (API), American Indian/Alaska Native/Other (AIANO), Black, Hispanic, and White patients. pCR and OS were modeled using logistic regression and Cox regression, respectively. Of 25,577 patients, Black patients achieved a 17.4% pCR rate, Hispanic 16.0%, White 14.7%, API 13.5%, and AIANO 10.9%. AIANO patients had lower odds of pCR than White patients (adjusted odds ratio, 0.66; 95% confidence interval [CI], 0.48-0.91). Among patients without pCR, API (adjusted hazard ratio [aHR], 0.62; 95% CI, 0.51-0.76) and Hispanic (aHR, 0.77; 95% CI, 0.67-0.89) patients had lower mortality risks than White patients. Among patients with pCR, similar OS rates were observed between Hispanic (aHR, 1.08; 95% CI, 0.66-1.78), Black (aHR, 0.77; 95% CI, 0.55-1.09), API (aHR, 0.41; 95% CI, 0.15-1.12), or AIANO (aHR, 0.35; 95% CI, 0.05-2.50) and White patients. Post-NACT pCR rates were similar across racial/ethnic groups of early-stage, ERBB2-low breast cancer patients. Among patients without pCR, API and Hispanic patients had better OS; among patients with pCR, there was no differential OS by race/ethnicity. Our findings suggest the need for longitudinal studies of OS differences in this patient population.

Lateral Canthotomy Task Trainer in an Educational Small Group for Flight Providers.

OBJECTIVE: Lateral canthotomy is a rare, emergent, vision-preserving procedure to treat orbital compartment syndrome. Using Ericsson's deliberate practice model, we aimed to develop a multimodal small group intervention including a modified low-fidelity task trainer to improve flight physician knowledge and technical competency for lateral canthotomy in the prehospital context. METHODS: Two cohorts of resident (postgraduate year 1) flight physicians received small group training during an all-day competency-based flight physician orientation. The first cohort completed self-report pre- and postintervention assessments. In the second cohort, examiners assessed pre- and postintervention performance. RESULTS: Comparing pre- and postintervention responses (N = 27), the mean agreement with the knowledge of indications increased from 3.7 to 4.8. The mean agreement regarding confidence in skills increased from 2.2 to 4.2 (P < .001). The majority of participants (20/27) indicated the trainer "definitely helped," whereas 7 of 27 residents indicated the trainer "somewhat helped" them to learn skills. Examiners assessed holistic learner performance (n = 13) as improved from a mean of 3.2 preintervention to 4.7 postintervention, with 11 of 13 learners demonstrating improvement (P < .005). CONCLUSION: We demonstrate the feasibility of a brief small group training combining multimodal didactics with a modified low-fidelity task trainer. Resident self-assessment and examiner assessment demonstrated improved procedural skill with lateral canthotomy.

A joint transcriptome-wide association study across multiple tissues identifies candidate breast cancer susceptibility genes.

Genome-wide association studies (GWASs) have identified more than 200 genomic loci for breast cancer risk, but specific causal genes in most of these loci have not been identified. In fact, transcriptome-wide association studies (TWASs) of breast cancer performed using gene expression prediction models trained in breast tissue have yet to clearly identify most target genes. To identify candidate genes, we performed a GWAS analysis in a breast cancer dataset from UK Biobank (UKB) and combined the results with the GWAS results of the Breast Cancer Association Consortium (BCAC) by a meta-analysis. Using the summary statistics from the meta-analysis, we performed a joint TWAS analysis that combined TWAS signals from multiple tissues. We used expression prediction models trained in 11 tissues that are potentially relevant to breast cancer from the Genotype-Tissue Expression (GTEx) data. In the GWAS analysis, we identified eight loci distinct from those reported previously. In the TWAS analysis, we identified 309 genes at 108 genomic loci to be significantly associated with breast cancer at the Bonferroni threshold. Of these, 17 genes were located in eight regions that were at least 1 Mb away from published GWAS hits. The remaining TWAS-significant genes were located in 100 known genomic loci from previous GWASs of breast cancer. We found that 21 genes located in known GWAS loci remained statistically significant after conditioning on previous GWAS index variants. Our study provides insights into breast cancer genetics through mapping candidate target genes in a large proportion of known GWAS loci and discovering multiple new loci.

Synonymous variants that disrupt messenger RNA structure are significantly constrained in the human population.

BACKGROUND: The role of synonymous single-nucleotide variants in human health and disease is poorly understood, yet evidence suggests that this class of "silent" genetic variation plays multiple regulatory roles in both transcription and translation. One mechanism by which synonymous codons direct and modulate the translational process is through alteration of the elaborate structure formed by single-stranded mRNA molecules. While tools to computationally predict the effect of non-synonymous variants on protein structure are plentiful, analogous tools to systematically assess how synonymous variants might disrupt mRNA structure are lacking. RESULTS: We developed novel software using a parallel processing framework for large-scale generation of secondary RNA structures and folding statistics for the transcriptome of any species. Focusing our analysis on the human transcriptome, we calculated 5 billion RNA-folding statistics for 469 million single-nucleotide variants in 45,800 transcripts. By considering the impact of all possible synonymous variants globally, we discover that synonymous variants predicted to disrupt mRNA structure have significantly lower rates of incidence in the human population. CONCLUSIONS: These findings support the hypothesis that synonymous variants may play a role in genetic disorders due to their effects on mRNA structure. To evaluate the potential pathogenic impact of synonymous variants, we provide RNA stability, edge distance, and diversity metrics for every nucleotide in the human transcriptome and introduce a "Structural Predictivity Index" (SPI) to quantify structural constraint operating on any synonymous variant. Because no single RNA-folding metric can capture the diversity of mechanisms by which a variant could alter secondary mRNA structure, we generated a SUmmarized RNA Folding (SURF) metric to provide a single measurement to predict the impact of secondary structure altering variants in human genetic studies.

Potential Impact of C-STAT for Prehospital Stroke Triage up to 24 Hours on a Regional Stroke System.

Background and Purpose: Thrombectomy for large vessel occlusion acute ischemic stroke (AIS-LVO) may benefit patients up to 24 hour since last known normal (LKN). Prehospital tools, like the Cincinnati Stroke Triage Assessment Tool (C-STAT), are used to select hospital destination for suspected AIS-LVO patients. The objective of this study was to estimate the potential impact of the expanded thrombectomy time window on suspected AIS-LVO cases transported to the regional comprehensive stroke center (CSC). Methods: From June to November 2015, C-STAT was performed by prehospital providers following a positive prehospital Cincinnati Prehospital Stroke Scale (CPSS) stroke screen in suspected stroke/TIA patients. There was no preferential triage based on C-STAT results. Final diagnoses, including the presence of AIS-LVO was ascertained via medical record review. Impact of positive C-STAT cases on CSC volumes was estimated for up to 24 hours since LKN. Results: Of 158 patients with prehospital suspicion for stroke/TIA, 105 were CPSS positive within 24 hours of onset and had complete C-STAT and clinical data available for analysis. Forty-six percent (17/37) of C-STAT + were non-strokes. C-STAT sensitivity and specificity for LVO were 71% (95% CI 36-92) and 67% (95% CI 58-80), respectively. C-STAT triage would increase transport of prehospital suspected stroke cases to the CSC by 11% (12/105) within six hours and 21% (22/105) within 24 hours. Of 37 C-STAT + patients, only 5 (13.5%) had LVO as final diagnosis. Conclusions: Preferential triage of prehospital suspected stroke patients using C-STAT would increase the number of patients transported to the CSC by 11% within six hours and an additional 10% from six to 24 hours. For every patient with LVO as final diagnosis, approximately an additional 6 non-LVO patients would be triaged to a CSC.