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1.
Am J Epidemiol ; 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-39010753

ABSTRACT

Etiologic heterogeneity occurs when distinct sets of events or exposures give rise to different subtypes of disease. Inference about subtype-specific exposure effects from two-phase outcome-dependent sampling data requires adjustment for both confounding and the sampling design. Common approaches to inference for these effects do not necessarily appropriately adjust for these sources of bias, or allow for formal comparisons of effects across different subtypes. Herein, using inverse probability weighting (IPW) to fit a multinomial model is shown to yield valid inference with this sampling design for subtype-specific exposure effects and contrasts thereof. The IPW approach is compared to common regression-based methods for assessing exposure effect heterogeneity using simulations. The methods are applied to estimate subtype-specific effects of various exposures on breast cancer risk in the Carolina Breast Cancer Study.

2.
Cancers (Basel) ; 16(13)2024 Jun 21.
Article in English | MEDLINE | ID: mdl-39001357

ABSTRACT

High intratumoral heterogeneity is thought to be a poor prognostic indicator. However, the source of heterogeneity may also be important, as genomic heterogeneity is not always reflected in histologic or 'visual' heterogeneity. We aimed to develop a predictor of histologic heterogeneity and evaluate its association with outcomes and molecular heterogeneity. We used VGG16 to train an image classifier to identify unique, patient-specific visual features in 1655 breast tumors (5907 core images) from the Carolina Breast Cancer Study (CBCS). Extracted features for images, as well as the epithelial and stromal image components, were hierarchically clustered, and visual heterogeneity was defined as a greater distance between images from the same patient. We assessed the association between visual heterogeneity, clinical features, and DNA-based molecular heterogeneity using generalized linear models, and we used Cox models to estimate the association between visual heterogeneity and tumor recurrence. Basal-like and ER-negative tumors were more likely to have low visual heterogeneity, as were the tumors from younger and Black women. Less heterogeneous tumors had a higher risk of recurrence (hazard ratio = 1.62, 95% confidence interval = 1.22-2.16), and were more likely to come from patients whose tumors were comprised of only one subclone or had a TP53 mutation. Associations were similar regardless of whether the image was based on stroma, epithelium, or both. Histologic heterogeneity adds complementary information to commonly used molecular indicators, with low heterogeneity predicting worse outcomes. Future work integrating multiple sources of heterogeneity may provide a more comprehensive understanding of tumor progression.

3.
Clin Cancer Res ; 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-39007881

ABSTRACT

PURPOSE: Immunotherapy (IO) in triple negative breast cancer (TNBC) has improved survival outcomes, with promising improvements in pCR rates among early high-risk HR+/HER2- breast cancers. However, biomarkers are needed to select patients likely to benefit from IO. MHC-I and tumor-specific MHC-II (tsMHC-II) expression are candidate biomarkers for PD-(L)1 checkpoint inhibition, but existing data from clinical trials included limited racial/ethnic diversity. METHODS: We performed multiplexed immunofluorescence assays in the Carolina Breast Cancer Study (CBCS, n=1628, 48% Black, 52% non-Black). Intrinsic subtype and P53 mutant-like status were identified using RNA-based multigene assays. We ranked participants based on tumoral MHC-I intensity (top 33% categorized as "MHC-IHigh") and MHC-II+ (≥5% of tumor cells as tsMHC-II+). MHC-I/II were evaluated in association with clinicopathological features by race. RESULTS: Black participants had higher frequency of TNBC (25% vs. 12.5%, p = < 0.001) and Basal-like (30% vs. 14%, p = < 0.001) tumors overall, and higher frequency of Basal-like (11% vs. 5.5%, p = 0.002) and TP53 mutant tumors (26% vs. 17%, p = 0.002) among HR+/HER2-. The frequency of tsMHC-II+ was higher in HR+/HER2- Black participants (7.9% vs. 4.9%, p = 0.04). Black participants also had higher frequency of MHC-Ihigh (38.7% vs. 28.2%, p <0.001), which was significant among HR+/HER2- (28.2% vs. 22.1%, p = 0.02). CONCLUSIONS: In this diverse study population, MHC-I and MHC-II tumor cell expression were more highly expressed in HR+/HER2- tumors from Black women, underscoring the importance of diverse and equitable enrollment in future IO trials.

4.
J Natl Cancer Inst ; 2024 Jul 17.
Article in English | MEDLINE | ID: mdl-39018167

ABSTRACT

BACKGROUND: Breast cancer is comprised of distinct molecular subtypes. Studies have reported differences in risk factor associations with breast cancer subtypes, especially by tumor estrogen receptor (ER) status, but their consistency across racial and ethnic populations has not been comprehensively evaluated. METHODS: We conducted a qualitative, scoping literature review using the Preferred Reporting Items for Systematic Reviews and Meta-analysis, extension for Scoping Reviews to investigate consistencies in associations between 18 breast cancer risk factors (reproductive, anthropometric, lifestyle, and medical history) and risk of ER-defined subtypes in women who self-identify as Asian, Black or African American, Hispanic or Latina, or White. We reviewed publications between January 1, 1990 and July 1, 2022. Etiologic heterogeneity evidence (convincing, suggestive, none, or inconclusive) was determined by expert consensus. RESULTS: Publications per risk factor ranged from 14 (benign breast disease history) to 66 (parity). Publications were most abundant for White women, followed by Asian, Black or African American, and Hispanic or Latina women. Etiologic heterogeneity evidence was strongest for parity, followed by age at first birth, post-menopausal BMI, oral contraceptive use, and estrogen-only and combined menopausal hormone therapy. Evidence was limited for other risk factors. Findings were consistent across racial and ethnic groups, although the strength of evidence varied. CONCLUSION: The literature supports etiologic heterogeneity by ER for some established risk factors that are consistent across race and ethnicity groups. However, in non-White populations evidence is limited. Larger, more comparable data in diverse populations is needed to better characterize breast cancer etiologic heterogeneity.

5.
Article in English | MEDLINE | ID: mdl-38980745

ABSTRACT

BACKGROUND: Fertility counseling is recommended for adolescent and young adult (AYA) women facing gonadotoxic cancer therapy. However, fertility care is subspecialized medical care offered at a limited number of institutions, making geographic access a potential barrier to guideline-concordant care. We assessed the relationship between geographic access and receipt of fertility counseling among AYA women with cancer. METHODS: Using data from the North Carolina Central Cancer Registry, we identified women diagnosed with lymphoma, gynecologic cancer, or breast cancer at ages 15-39 years during 2004-2015. Eligible women were invited to complete an online survey on various topics, including fertility counseling. Geographic access was measured, using geocoded addresses, as vehicular travel time from residence to the nearest fertility clinic available at diagnosis. Multivariable regression models were used to examine the association between travel time and receipt of fertility counseling by provider type: health care provider vs fertility specialist. RESULTS: Analyses included 380 women. Median travel time to a fertility clinic was 31 (IQR: 17-71) minutes. Overall, 75% received fertility counseling from a health care provider and 16% by a fertility specialist. Women who lived ≥30 minutes from a clinic were 13% less likely to receive fertility counseling by a health care provider (PR:0.87; 95% CI:0.75-1.00) and 49% less likely to receive counseling by a fertility specialist (PR:0.51; 95% CI:0.28-0.93). CONCLUSIONS: Women who lived further away from fertility clinics were less likely to receive fertility counseling. IMPACT: Interventions to improve access to fertility counseling should include strategies to alleviate the burden of geographic access.

6.
JCO Precis Oncol ; 8: e2400137, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39013134

ABSTRACT

PURPOSE: Genomic tests, such as the Oncotype Dx 21-gene and Prosigna risk of recurrence (ROR-P) assay, are commonly used for breast cancer prognostication. Emerging data suggest variability between assays, but this has not been compared in diverse populations. MATERIALS AND METHODS: RNA sequencing was performed on 647 previously untreated stage I-III estrogen receptor-positive/human epidermal growth factor receptor 2-negative tumors in the Carolina Breast Cancer Study, which oversampled Black and younger women (age <50 years at diagnosis), using research versions of two common RNA-based prognostic assays: ROR-PR and the 21-gene recurrence score (RSR). Relative frequency differences and 95% CIs were estimated for associations with race and age, and hazards of 5-year local or distant recurrence were modeled with Cox regression. Proliferation and estrogen module scores from each assay, representing broad activity of genes in those pathways, were examined to guide interpretation of differences between tests. RESULTS: Among both younger and older individuals, Black women had higher frequency of intermediate and high ROR-PR scores than non-Black women. Race was not significantly associated with RSR in either age group. High (hazard ratio [HR], 4.67 [95% CI, 1.73 to 12.70]) and intermediate (HR, 2.12 [95% CI, 0.98 to 4.62]) ROR-PR scores were associated with greater risk of recurrence, but RSR did not predict recurrence. RSR emphasized estrogen over proliferation modules, whereas ROR-PR emphasized proliferation. Higher proliferation scores were associated with younger age and Black race in both assays. Modifications to the RSR algorithm that increased emphasis on proliferation improved prognostication in this diverse population. CONCLUSION: ROR-PR and the 21-gene RSR differentially emphasize estrogen-related and proliferative biology. The emphasis of 21-gene RS on estrogen-related biology and lower endocrine therapy initiation among Black women may contribute to poorer prognostic ability in heterogeneously treated populations.


Subject(s)
Breast Neoplasms , Neoplasm Recurrence, Local , Humans , Female , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Middle Aged , Adult , Neoplasm Recurrence, Local/genetics , Black or African American/genetics , Age Factors , Aged , Prognosis
7.
Cancer Res ; 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38832928

ABSTRACT

Breast cancer includes several subtypes with distinct characteristic biological, pathological, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate development of improved prevention and treatment approaches. Here, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case GWAS (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared to luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to 2-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among breast cancer patients. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC.

8.
Nat Genet ; 56(5): 819-826, 2024 May.
Article in English | MEDLINE | ID: mdl-38741014

ABSTRACT

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.


Subject(s)
Black People , Breast Neoplasms , Genetic Predisposition to Disease , Genome-Wide Association Study , Polymorphism, Single Nucleotide , Humans , Female , Genome-Wide Association Study/methods , Breast Neoplasms/genetics , Black People/genetics , Case-Control Studies , Risk Factors , Triple Negative Breast Neoplasms/genetics , Alleles , Multifactorial Inheritance/genetics , Middle Aged , Genetic Loci , White People/genetics
9.
Nat Commun ; 15(1): 3718, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38697998

ABSTRACT

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.


Subject(s)
Breast Neoplasms , Genetic Predisposition to Disease , Transcriptome , Adult , Aged , Female , Humans , Middle Aged , Black People/genetics , Breast Neoplasms/genetics , Case-Control Studies , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genome-Wide Association Study , Polymorphism, Single Nucleotide , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolism , Black or African American , United States
10.
Article in English | MEDLINE | ID: mdl-38642278

ABSTRACT

PURPOSE: Emotional and functional well-being (EWB and FWB) are important components of mental health and quality of life. This study aims to evaluate long-term EWB and FWB in breast cancer (BC) survivors. METHODS: The Carolina Breast Cancer Study Phase 3 oversampled Black and younger (< 50 years in age) women so that they each represent approximately 50% of the study population and assessed participants' EWB and FWB with the Functional Assessment of Cancer Therapy-Breast (FACT-B) at 5- (baseline), 25-, and 84-months post diagnosis. Multinomial logit models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between demographic and clinical characteristics and well-being change relative to baseline. RESULTS: Among 2,781 participants with BC, average EWB and FWB improved with time since diagnosis. Persistent FWB decrements were associated with Black race [OR 1.4 (95% CI 1.2-1.7) and 1.3 (95% CI 1.1-1.6), at 25-months and 84-months respectively], older age [OR 1.4 (95% CI 1.1-1.7) and 1.5 (95% CI 1.2-1.8), respectively], no chemotherapy, and recurrence [OR 2.9 (95% CI 1.8-4.8) and 3.1 (95% CI 2.1-4.6), respectively]. EWB decrements were associated with advanced stage and recurrence. Decrements in combined (FWB+EWB) well-being were associated with recurrence at both follow-up survey timepoints [ORs 4.7 (95% CI 2.7-8.0) and 4.3 (95% CI 2.8-6.6), respectively]. CONCLUSIONS: Long-term well-being varies by demographics and clinical features, with Black women and women with aggressive disease at greatest risk of long-term decrements.

11.
Breast Cancer Res ; 26(1): 50, 2024 Mar 21.
Article in English | MEDLINE | ID: mdl-38515208

ABSTRACT

PURPOSE: Survivin/BIRC5 is a proliferation marker that is associated with poor prognosis in breast cancer and an attractive therapeutic target. However, BIRC5 has not been well studied among racially diverse populations where aggressive breast cancers are prevalent. EXPERIMENTAL DESIGN: We studied BIRC5 expression in association with clinical and demographic variables and as a predictor of recurrence in 2174 participants in the Carolina Breast Cancer Study (CBCS), a population-based study that oversampled Black (n = 1113) and younger (< 50 years; n = 1137) participants with breast cancer. For comparison, similar analyses were conducted in The Cancer Genome Atlas [TCGA N = 1094, Black (n = 183), younger (n = 295)]. BIRC5 was evaluated as a continuous and categorical variable (highest quartile vs. lower three quartiles). RESULTS: Univariate, continuous BIRC5 expression was higher in breast tumors from Black women relative to non-Black women in both estrogen receptor (ER)-positive and ER-negative tumors and in analyses stratified by stage (i.e., within Stage I, Stage II, and Stage III/IV tumors). Within CBCS and TCGA, BIRC5-high was associated with young age (< 50 years) and Black race, as well as hormone receptor-negative tumors, non-Luminal A PAM50 subtypes, advanced stage, and larger tumors (> 2 cm). Relative to BIRC5-low, BIRC5-high tumors were associated with poor 5-year recurrence-free survival (RFS) among ER-positive tumors, both in unadjusted models [HR (95% CI): 2.7 (1.6, 4.6)] and after adjustment for age and stage [Adjusted HR (95% CI): 1.87 (1.07, 3.25)]. However, this relationship was not observed among ER-negative tumors [Crude HR (95% CI): 0.7 (0.39, 1.2); Adjusted HR (95% CI): 0.67 (0.37, 1.2)]. CONCLUSION: Black and younger women with breast cancer have a higher burden of BIRC5-high tumors than older and non-Black women. Emerging anti-survivin treatment strategies may be an important future direction for equitable breast cancer outcomes.


Subject(s)
Breast Neoplasms , Female , Humans , Middle Aged , Breast Neoplasms/pathology , Survivin/genetics , Black or African American
12.
Cancer Epidemiol Biomarkers Prev ; 33(5): 721-730, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38426904

ABSTRACT

BACKGROUND: Somatic mutational signatures elucidate molecular vulnerabilities to therapy, and therefore detecting signatures and classifying tumors with respect to signatures has clinical value. However, identifying the etiology of the mutational signatures remains a statistical challenge, with both small sample sizes and high variability in classification algorithms posing barriers. As a result, few signatures have been strongly linked to particular risk factors. METHODS: Here, we develop a statistical model, Diffsig, for estimating the association of one or more continuous or categorical risk factors with DNA mutational signatures. Diffsig takes into account the uncertainty associated with assigning signatures to samples as well as multiple risk factors' simultaneous effect on observed DNA mutations. RESULTS: We applied Diffsig to breast cancer data to assess relationships between five established breast-relevant mutational signatures and etiologic variables, confirming known mechanisms of cancer development. In simulation, our model was capable of accurately estimating expected associations in a variety of contexts. CONCLUSIONS: Diffsig allows researchers to quantify and perform inference on the associations of risk factors with mutational signatures. IMPACT: We expect Diffsig to provide more robust associations of risk factors with signatures to lead to better understanding of the tumor development process and improved models of tumorigenesis.


Subject(s)
Breast Neoplasms , Mutation , Humans , Risk Factors , Female , Breast Neoplasms/genetics , Models, Statistical , Algorithms
13.
Hum Mol Genet ; 33(8): 687-697, 2024 Apr 08.
Article in English | MEDLINE | ID: mdl-38263910

ABSTRACT

BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.


Subject(s)
Black People , Breast Neoplasms , Genetic Predisposition to Disease , Female , Humans , Black People/genetics , Breast Neoplasms/genetics , Genome-Wide Association Study , Polymorphism, Single Nucleotide
14.
Cancer Causes Control ; 35(5): 825-837, 2024 May.
Article in English | MEDLINE | ID: mdl-38217760

ABSTRACT

PURPOSE: Screening history influences stage at detection, but regular preventive care may also influence breast tumor diagnostic characteristics. Few studies have evaluated healthcare utilization (both screening and primary care) in racially diverse screening-eligible populations. METHODS: This analysis included 2,058 women age 45-74 (49% Black) from the Carolina Breast Cancer Study, a population-based cohort of women diagnosed with invasive breast cancer between 2008 and 2013. Screening history (threshold 0.5 mammograms per year) and pre-diagnostic healthcare utilization (i.e. regular care, based on responses to "During the past ten years, who did you usually see when you were sick or needed advice about your health?") were assessed as binary exposures. The relationship between healthcare utilization and tumor characteristics were evaluated overall and race-stratified. RESULTS: Among those lacking screening, Black participants had larger tumors (5 + cm) (frequency 19.6% vs 11.5%, relative frequency difference (RFD) = 8.1%, 95% CI 2.8-13.5), but race differences were attenuated among screening-adherent participants (10.2% vs 7.0%, RFD = 3.2%, 0.2-6.2). Similar trends were observed for tumor stage and mode of detection (mammogram vs lump). Among all participants, those lacking both screening and regular care had larger tumors (21% vs 8%, RR = 2.51, 1.76-3.56) and advanced (3B +) stage (19% vs 6%, RR = 3.15, 2.15-4.63) compared to the referent category (screening-adherent and regular care). Under-use of regular care and screening was more prevalent in socioeconomically disadvantaged areas of North Carolina. CONCLUSIONS: Access to regular care is an important safeguard for earlier detection. Our data suggest that health equity interventions should prioritize both primary care and screening.


Subject(s)
Breast Neoplasms , Early Detection of Cancer , Healthcare Disparities , Humans , Female , Breast Neoplasms/diagnosis , Breast Neoplasms/ethnology , Middle Aged , Aged , Early Detection of Cancer/statistics & numerical data , Healthcare Disparities/statistics & numerical data , Healthcare Disparities/ethnology , North Carolina/epidemiology , Mammography/statistics & numerical data , Patient Acceptance of Health Care/statistics & numerical data , Patient Acceptance of Health Care/ethnology , Black or African American/statistics & numerical data , Cohort Studies , White People/statistics & numerical data , Mass Screening/statistics & numerical data , Mass Screening/methods
15.
Cancer Epidemiol Biomarkers Prev ; 33(5): 654-661, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38270534

ABSTRACT

BACKGROUND: OncotypeDx is a prognostic and predictive genomic assay used in early-stage hormone receptor-positive, HER2- (HR+/HER2-) breast cancer. It is used to inform adjuvant chemotherapy decisions, but not all eligible women receive testing. We aimed to assess variation in testing by demographics and geography, and to determine whether testing was associated with chemotherapy. METHODS: For 1,615 women in the Carolina Breast Cancer Study with HR+/HER2-, Stage I-II tumors, we estimated prevalence differences (PD) and 95% confidence intervals (CI) for receipt of OncotypeDx genomic testing in association with and sociodemographic characteristics. We assessed associations between testing and chemotherapy receipt overall and by race. Finally, we calculated the proportion of eligible women receiving OncotypeDx by county-level rurality, census tract-level socioeconomic status, and Area Health Education Center regions. RESULTS: 38% (N = 609) of potentially eligible women were tested, with lower testing prevalences in Black (31%; PD, -11%; 95% CI, -16%-6%) and low-income women (24%; PD, -20%; 95% CI, -29% to -11%) relative to non-Black and higher income women. Urban participants were less likely to be tested than rural participants, though this association varied by region. Among women with low genomic risk tumors, tested participants were 29% less likely to receive chemotherapy than untested participants (95% CI, -40% to -17%). Racial differences in chemotherapy were restricted to untested women. CONCLUSIONS: Both individual and area-level socioeconomics predict likelihood of OncotypeDx testing. IMPACT: Variable adoption of OncotypeDx by socioeconomics and across geographic settings may contribute to excess chemotherapy among patients with HR+/HER2- cancers. See related In the Spotlight, p. 635.


Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Middle Aged , Adult , Aged , Social Class , Healthcare Disparities/statistics & numerical data , Genetic Testing/statistics & numerical data , Genetic Testing/methods , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/genetics
16.
PLoS One ; 19(1): e0283884, 2024.
Article in English | MEDLINE | ID: mdl-38252639

ABSTRACT

BACKGROUND: Latent class analysis (LCA) identifies distinct groups within a heterogeneous population, but its application to accelerometry-assessed physical activity and sedentary behavior has not been systematically explored. We conducted a systematic scoping review to describe the application of LCA to accelerometry. METHODS: Comprehensive searches in PubMed, Web of Science, CINHAL, SPORTDiscus, and Embase identified studies published through December 31, 2021. Using Covidence, two researchers independently evaluated inclusion criteria and discrepancies were resolved by consensus. Studies with LCA applied to accelerometry or combined accelerometry/self-reported measures were selected. Data extracted included study characteristics and both accelerometry and LCA methods. RESULTS: Of 2555 papers found, 66 full-text papers were screened, and 12 papers (11 cross-sectional, 1 cohort) from 8 unique studies were included. Study sample sizes ranged from 217-7931 (mean 2249, standard deviation 2780). Across 8 unique studies, latent class variables included measures of physical activity (100%) and sedentary behavior (75%). About two-thirds (63%) of the studies used accelerometry only and 38% combined accelerometry and self-report to derive latent classes. The accelerometer-based variables in the LCA model included measures by day of the week (38%), weekday vs. weekend (13%), weekly average (13%), dichotomized minutes/day (13%), sex specific z-scores (13%), and hour-by-hour (13%). The criteria to guide the selection of the final number of classes and model fit varied across studies, including Bayesian Information Criterion (63%), substantive knowledge (63%), entropy (50%), Akaike information criterion (50%), sample size (50%), Bootstrap likelihood ratio test (38%), and visual inspection (38%). The studies explored up to 5 (25%), 6 (38%), or 7+ (38%) classes, ending with 3 (50%), 4 (13%), or 5 (38%) final classes. CONCLUSIONS: This review explored the application of LCA to physical activity and sedentary behavior and identified areas of improvement for future studies leveraging LCA. LCA was used to identify unique groupings as a data reduction tool, to combine self-report and accelerometry, and to combine different physical activity intensities and sedentary behavior in one LCA model or separate models.


Subject(s)
Accelerometry , Sedentary Behavior , Female , Male , Humans , Bayes Theorem , Cross-Sectional Studies , Latent Class Analysis , Exercise
17.
Breast Cancer Res Treat ; 204(1): 107-116, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38070094

ABSTRACT

BACKGROUND: Breast cancer chemotherapy utilization not only may differ by race and age, but also varies by genomic risk, tumor characteristics, and patient characteristics. Studies in demographically diverse populations with both clinical and genomic data are necessary to understand potential disparities by race and age. METHODS: In the Carolina Breast Cancer Study Phase 3 (2008-2013), chemotherapy receipt (yes/no) and regimen type were assessed in association with age and race among hormone receptor (HR) positive and HER2-negative tumors (n = 1862). Odds ratios were estimated for the association between demographic factors and chemotherapy receipt. RESULTS: Monotonic decreases in frequency of adjuvant chemotherapy receipt were observed over time during the study period, while neoadjuvant chemotherapy was stable. Younger age was associated with chemotherapy receipt (OR [95% CI]: 2.9 [2.4, 3.6]) and with anthracycline-based regimens (OR [95% CI]: 1.7 [1.3, 2.4]). Participants who had Medicaid (OR [95% CI]: 1.8 [1.3, 2.5]), lived in rural settings (OR [95% CI]: 1.4 [1.0, 2.0]), or were Black (OR [95% CI]: 1.5 [1.2, 1.8]) had slightly higher odds of chemotherapy, but these associations were non-significant with adjustment for stage and grade. Associations between younger age and chemotherapy receipt were strongest among women who did not receive genomic testing. CONCLUSIONS: While race was not strongly associated with chemotherapy receipt, younger age remains a strong predictor of chemotherapy receipt, even with adjustment for clinical factors and among women who receive genomic testing.


Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast/pathology , Chemotherapy, Adjuvant , Neoadjuvant Therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Receptor, ErbB-2/genetics
18.
Cancer J ; 29(6): 316-322, 2023.
Article in English | MEDLINE | ID: mdl-37963365

ABSTRACT

PURPOSE: Racial disparities in outcomes of breast cancer in the United States have widened over more than 3 decades, driven by complex biologic and social factors. In this review, we summarize the biological and social narratives that have shaped breast cancer disparities research across different scientific disciplines in the past, explore the underappreciated but crucial ways in which these 2 strands of the breast cancer story are interwoven, and present 5 key strategies for creating transformative interdisciplinary research to achieve equity in breast cancer treatment and outcomes. DESIGN: We first review the key differences in tumor biology in the United States between patients racialized as Black versus White, including the overrepresentation of triple-negative breast cancer and differences in tumor histologic and molecular features by race for hormone-sensitive disease. We then summarize key social factors at the interpersonal, institutional, and social structural levels that drive inequitable treatment. Next, we explore how biologic and social determinants are interwoven and interactive, including historical and contemporary structural factors that shape the overrepresentation of triple-negative breast cancer among Black Americans, racial differences in tumor microenvironment, and the complex interplay of biologic and social drivers of difference in outcomes of hormone receptor positive disease, including utilization and effectiveness of endocrine therapies and the role of obesity. Finally, we present 5 principles to increase the impact and productivity of breast cancer equity research. RESULTS: We find that social and biologic drivers of breast cancer disparities are often cyclical and are found at all levels of scientific investigation from cells to society. To break the cycle and effect change, we must acknowledge and measure the role of structural racism in breast cancer outcomes; frame biologic, psychosocial, and access factors as interwoven via mechanisms of cumulative stress, inflammation, and immune modulation; take responsibility for the impact of representativeness (or the lack thereof) in genomic and decision modeling on the ability to accurately predict the outcomes of Black patients; create research that incorporates the perspectives of people of color from inception to implementation; and rigorously evaluate innovations in equitable cancer care delivery and health policies. CONCLUSIONS: Innovative, cross-disciplinary research across the biologic and social sciences is crucial to understanding and eliminating disparities in breast cancer outcomes.


Subject(s)
Health Equity , Racism , Triple Negative Breast Neoplasms , Humans , Black or African American , Delivery of Health Care , Tumor Microenvironment , United States , Health Status Disparities , Healthcare Disparities
19.
NPJ Breast Cancer ; 9(1): 92, 2023 Nov 11.
Article in English | MEDLINE | ID: mdl-37952058

ABSTRACT

Approaches for rapidly identifying patients at high risk of early breast cancer recurrence are needed. Image-based methods for prescreening hematoxylin and eosin (H&E) stained tumor slides could offer temporal and financial efficiency. We evaluated a data set of 704 1-mm tumor core H&E images (2-4 cores per case), corresponding to 202 participants (101 who recurred; 101 non-recurrent matched on age and follow-up time) from breast cancers diagnosed between 2008-2012 in the Carolina Breast Cancer Study. We leveraged deep learning to extract image information and trained a model to identify recurrence. Cross-validation accuracy for predicting recurrence was 62.4% [95% CI: 55.7, 69.1], similar to grade (65.8% [95% CI: 59.3, 72.3]) and ER status (66.3% [95% CI: 59.8, 72.8]). Interestingly, 70% (19/27) of early-recurrent low-intermediate grade tumors were identified by our image model. Relative to existing markers, image-based analyses provide complementary information for predicting early recurrence.

20.
Nucleic Acids Res ; 51(19): 10568-10589, 2023 10 27.
Article in English | MEDLINE | ID: mdl-37739411

ABSTRACT

Stringent control of centrosome duplication and separation is important for preventing chromosome instability. Structural and numerical alterations in centrosomes are hallmarks of neoplastic cells and contribute to tumorigenesis. We show that a Centrosome Amplification 20 (CA20) gene signature is associated with high expression of the Tripartite Motif (TRIM) family member E3 ubiquitin ligase, TRIM69. TRIM69-ablation in cancer cells leads to centrosome scattering and chromosome segregation defects. We identify Serine/threonine-protein kinase 3 (MST2) as a new direct binding partner of TRIM69. TRIM69 redistributes MST2 to the perinuclear cytoskeleton, promotes its association with Polo-like kinase 1 (PLK1) and stimulates MST2 phosphorylation at S15 (a known PLK1 phosphorylation site that is critical for centrosome disjunction). TRIM69 also promotes microtubule bundling and centrosome segregation that requires PRC1 and DYNEIN. Taken together, we identify TRIM69 as a new proximal regulator of distinct signaling pathways that regulate centrosome dynamics and promote bipolar mitosis.


Subject(s)
Centrosome , Chromosome Segregation , Signal Transduction , Cell Cycle Proteins/metabolism , Centrosome/metabolism , Mitosis/genetics , Phosphorylation , Spindle Apparatus/metabolism
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