Chronic Health Conditions, Disability, and Physical and Cognitive Limitations Among LGBTQ+ Cancer Survivors.

BACKGROUND: Cancer survivors are at high risk for chronic health conditions and physical and cognitive limitations. However, few studies have explored these outcomes among LGBTQ+ survivors. METHODS: We used pooled, weighted Behavioral Risk Factor Surveillance System data from 23 states that completed two specific modules from 2020-2022. We calculated age-adjusted prevalence for heart disease, asthma, COPD, depressive disorders, myocardial infarction, kidney disease, stroke, diabetes, hearing disability, vision disability, cognitive limitations, and difficulty walking, dressing, and running errands in LGBTQ+, lesbian, gay, or bisexual (LGB), transgender or gender non-conforming (TGNC), and non-LGBTQ+ cancer survivors. Four multivariable logistic regression models controlling for different factors were run for each outcome. RESULTS: Of 40,990 cancer survivors, 1,715 were LGBTQ+. LGBTQ+ survivors had significantly higher age-adjusted prevalence of all outcomes. The prevalence of all outcomes was highest among TGNC survivors except for depressive disorders and cognitive limitations. LGBTQ+ survivors had higher odds of reporting asthma (aOR: 1.5, 95%CI:1.2-1.9), depressive disorders (aOR: 1.9, 95%CI:1.6-2.4), kidney disease (aOR: 1.5, 95%CI:1.1-2.1), stroke (aOR: 1.7, 95%CI:1.3-2.3), diabetes (aOR: 1.3, 95%CI:1.0-1.6), vision disability (aOR: 1.6, 95%CI:1.2-2.2), cognitive limitations (aOR: 2.3, 95%CI:1.8-2.9), difficulty walking (aOR: 1.7, 95%CI:1.3-2.0), dressing (aOR: 2.0, 95%CI:1.5-2.7), and running errands (aOR: 1.6, 95%CI:1.3-2.1). In TGNC models, TGNC cancer survivors had increased odds of most outcomes. CONCLUSIONS: LGBTQ+ cancer survivors have an elevated burden of all chronic health conditions, disabilities, and limitations assessed. TGNC cancer survivors experience even higher burden of the same outcomes. IMPACT: Findings highlight substantial disparities regarding the health of LGBTQ+ cancer survivors.

Cigarette smoking and prostate cancer aggressiveness among African and European American men.

PURPOSE: Smoking is a modifiable lifestyle factor that has not been established as a prostate cancer risk factor, nor emphasized in prostate cancer prevention. Studies have shown that African American (AA) smokers have a poorer cancer prognosis than European Americans (EAs), while having a lower prevalence of heavy smoking. We examined the relationship between cigarette smoking and prostate cancer aggressiveness and assessed racial differences in smoking habits on the probability of high-aggressive prostate cancer. METHODS: Using data from the North Carolina-Louisiana Prostate Cancer Project (n = 1,279), prostate cancer aggressiveness was defined as high or low based on Gleason scores, serum prostate-specific antigen levels, and tumor stage. Cigarette smoking was categorized as current, former, or never smokers. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Self-reported current (OR = 1.99; 95% CI 1.30-3.06) smoking was associated with high-aggressive prostate cancer relative to never smokers. When stratified by self-reported race, the odds of having high-aggressive cancer increased among AA current (OR = 3.58; 95% CI 2.04-6.28) and former smokers (OR = 2.21; 95% CI 1.38-3.53) compared to AA never smokers, but the odds were diminished among the EA stratum (Pself-reported race x smoking status = 0.003). CONCLUSION: Cigarette smoking is associated with prostate cancer aggressiveness, a relationship modulated by self-reported race. Future research is needed to investigate types of cigarettes smoked and metabolic differences that may be contributing to the racial disparities observed.

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.

Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.

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.

Understanding mechanisms of racial disparities in breast cancer: an assessment of screening and regular care in the Carolina Breast Cancer Study.

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.

Individual and Neighborhood-level Socioeconomic Status and Somatic Mutations Associated With Increased Risk of Cardiovascular Disease and Mortality: A Cross-Sectional Analysis in the Women's Health Initiative.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of leukemogenic mutations in white blood cells, has been associated with increased risk of atherosclerotic cardiovascular diseases, cancer, and mortality. OBJECTIVE: We examined the relationship between individual- and neighborhood-level socioeconomic status (SES) and CHIP and evaluated effect modification by interpersonal and intrapersonal resources. METHODS: The study population included 10,799 postmenopausal women from the Women's Health Initiative without hematologic malignancy or antineoplastic medication use. Individual- and neighborhood (Census tract)-level SES were assessed across several domains including education, income, and occupation, and a neighborhood-level SES summary z-score, which captures multiple dimensions of SES, was generated. Interpersonal and intrapersonal resources were self-reports. CHIP was ascertained based on a prespecified list of leukemogenic driver mutations. Weighted logistic regression models adjusted for covariates were used to estimate risk of CHIP as an odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: The interval-scale neighborhood-level SES summary z-score was associated with a 3% increased risk of CHIP: OR (95% CI) = 1.03 (1.00-1.05), p = .038. Optimism significantly modified that estimate, such that among women with low/medium and high levels of optimism, the corresponding ORs (95% CIs) were 1.03 (1.02-1.04) and 0.95 (0.94-0.96), pInteraction < .001. CONCLUSIONS: Our findings suggest that reduced risk of somatic mutation may represent a biological pathway by which optimism protects contextually advantaged but at-risk women against age-related chronic disease and highlight potential benefits of long-term, positive psychological interventions.

Linking African ancestral substructure to prostate cancer health disparities.

Prostate cancer (PCa) is a significant health burden in Sub-Saharan Africa, with mortality rates loosely linked to African ancestry. Yet studies aimed at identifying contributing risk factors are lacking within the continent and as such exclude for significant ancestral diversity. Here, we investigate a series of epidemiological demographic and lifestyle risk factors for 1387 men recruited as part of the multi-ethnic Southern African Prostate Cancer Study (SAPCS). We found poverty to be a decisive factor for disease grade and age at diagnosis, with other notably significant PCa associated risk factors including sexually transmitted diseases, erectile dysfunction, gynaecomastia, and vertex or complete pattern balding. Aligned with African American data, Black ethnicity showed significant risk for PCa diagnosis (OR = 1.44, 95% CI 1.05-2.00), and aggressive disease presentation (ISUP ≥ 4: OR = 2.25, 95% CI 1.49-3.40). New to this study, we demonstrate African ancestral population substructure associated PCa disparity, observing increased risk for advanced disease for the southern African Tsonga people (ISUP ≥ 4: OR = 3.43, 95% CI 1.62-7.27). Conversely, South African Coloured were less likely to be diagnosed with aggressive disease overall (ISUP ≥ 3: OR = 0.38, 95% 0.17-0.85). Understanding the basis for PCa health disparities calls for African inclusion, however, lack of available data has limited the power to begin discussions. Here, focusing on arguably the largest study of its kind for the African continent, we draw attention to the contribution of within African ancestral diversity as a contributing factor to PCa health disparities within the genetically diverse region of southern Africa.

Breast exam use during the protracted COVID-19 pandemic, by age, race, and geography.

In this study we analyzed data collected from the onset of the COVID-19 pandemic through March 31, 2022, to identify temporal shifts in breast exam volume. Screening mammography volume stabilized toward the end of the study period, and diagnostic exam volume varied over time and by age. Older women experienced a decline in diagnostic exam volume between August 2020 and April 2021 that was not observed among women aged younger than 50 years (50-69 years: monthly percentage change [MPC] = -6.5%; and 70 years and older: MPC = -15.7%). With respect to breast biopsy volume, women aged younger than 70 years had increased exam volume beginning in April 2020 and June 2020, whereas a corresponding increase among older women was delayed until April 2021 (70 years and older: MPC = 9.3%). Findings from our study suggest a temporal shift in the use of breast exams that could result in differential detection of breast cancer by age.

Testosterone therapy and cancer risks among men in the SEER-Medicare linked database.

BACKGROUND: We examined associations between two forms of testosterone therapy (TT) and risks of seven cancers among men. METHODS: SEER-Medicare combines cancer registry data from the Surveillance, Epidemiology, and End Results programme with Medicare claims. Our population-based case-control study included incident cancer cases diagnosed between 1992-2015: prostate (n = 130,713), lung (n = 105,466), colorectal (n = 56,433), bladder (n = 38,873), non-Hodgkin lymphoma (n = 17,854), melanoma (n = 14,241), and oesophageal (n = 9116). We selected 100,000 controls from a 5% random sample of Medicare beneficiaries and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: TT was associated with lower risk of distant-stage prostate cancer (injection/implantation OR = 0.72, 95% CI: 0.60-0.86; topical OR = 0.50, 95% CI: 0.24-1.03). We also observed inverse associations for distant-stage colorectal cancer (injection/implantation OR = 0.75, 95% CI: 0.62-0.90; topical OR = 0.11, 95% CI: 0.05-0.24). Risks of distant-stage colorectal and prostate cancers decreased with time after initiating TT by injection/implantation. By contrast, TT was positively associated with distant-stage melanoma (injection/implantation OR = 1.70, 95% CI: 1.37-2.11). TT was not associated with bladder cancer, oesophageal cancer, lung cancer or non-Hodgkin lymphoma. CONCLUSION: TT was inversely associated with distant-stage prostate and colorectal cancers but was positively associated with distant-stage melanoma. These observations may suggest an aetiologic role for TT or the presence of residual confounding.

Redefining precision cancer prevention to promote health equity.

Precision cancer prevention as it is currently envisioned is a targeted, molecular-based approach to intercept carcinogenesis before cancer develops or before it becomes untreatable. Unfortunately, due to systemic biases, current precision cancer prevention interventions might not be effective in all populations, especially in minoritized communities. In addition, not all cancer risk is attributable to genetic or even biological factors, but includes social determinants of health (SDH). Here, we propose a broader framework for precision cancer prevention, anchored in optimizing the benefits to harms for all people. We propose that precision cancer prevention considers not only what is being delivered, but also for whom, where, and how, with a goal of achieving cancer prevention health equity.

Oncologist-Reported Reasons for Not Ordering Multimarker Tumor Panels: Results From a Nationally Representative Survey.

This study examines oncologist-reported reasons for not using multimarker tumor panel testing and the association between these reasons and oncologist-level, facility-level, and patient-mix characteristics. METHODS: We used data collected from a nationally representative sample (N = 1,281) of medical oncologists participating in the National Cancer Institute's National Survey of Precision Medicine in Cancer Treatment. RESULTS: In addition to testing not being seen as relevant (87%) and no evidence of test utility (77%), the most frequently reported reasons for not ordering a multimarker tumor panel test was difficulty in obtaining sufficient tissue (57%) and using individual gene tests (72%). These reasons were more likely to be reported by oncologists practicing in rural clinics and less likely to be reported by oncologists with an academic affiliation or with access to genetic services such as on-site genetic counselors and internal genetic testing policies. CONCLUSION: Modifiable, organizational factors were associated with ordering multimarker tumor panels. Receipt of genomics training and organizational policies related to the use of genomics were associated with lower reporting of barriers to ordering multimarker tumor panels, pointing to potential targets for future studies aimed at increasing appropriate multimarker tumor panel testing in cancer treatment management.

An Up-to-date Assessment of US Prostate Cancer Incidence Rates by Stage and Race: A Novel Approach Combining Multiple Imputation with Age and Delay Adjustment.

BACKGROUND: In the USA, it is unknown whether metastatic prostate cancer incidence has continued to increase and whether racial differences have persisted. OBJECTIVE: Combining multiple imputation with age and delay adjustment, we provide an up-to-date, comprehensive assessment of US prostate cancer incidence trends by stage and race. DESIGN, SETTING, AND PARTICIPANTS: From Surveillance Epidemiology and End Results (SEER)-18, 774 240 prostate cancer cases were diagnosed during 2004-2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multiple imputation assigned prostate cancer stage to the 4.7% of cases with missing stage, which varied by year and race-ethnicity. SEER delay factors adjusted case counts to anticipated future data corrections. Twenty datasets were imputed, and Rubin's rules were used for summary estimation. Overall and stage-specific rates were estimated and stratified by race and age group. Joinpoint software identified significant temporal changes and estimated annual percentage changes. We compared these estimates without multiple imputation and delay adjustment. RESULTS AND LIMITATIONS: Metastatic prostate cancer incidence increased during 2011-2017, with an annual percentage change of 5.5. This was followed by increases in localized and regional disease since 2014. Non-Hispanic black men continued to have the highest incidence, especially for metastatic disease. The increasing rate of metastatic prostate cancer in non-Hispanic white men aged 50-74 yr accelerated recently, and the incidence was 56% higher in 2017 than in 2004. Rates without multiple imputation and delay adjustment were quantitatively and qualitatively different. This observational study is unable to assign causes to observed changes in prostate cancer incidence. CONCLUSIONS: Multiple imputation and delay adjustment are essential for portraying accurately stage- and race-specific prostate cancer incidence as clinical practice evolves. PATIENT SUMMARY: In the USA, diagnosis of prostate cancer that has spread to distant sites (metastatic disease) continues to increase. Black men continue to have higher risks of being diagnosed with metastatic prostate cancer than other race-ethnicities.

Involving patients and their families in deciding to use next generation sequencing: Results from a nationally representative survey of U.S. oncologists.

OBJECTIVE: Next generation sequencing (NGS) may aid in tumor classification and treatment. Barriers to shared decision-making may influence use of NGS. We examined, from oncologists' perspectives, whether barriers to involving patients/families in decision-making were associated with NGS use. METHODS: Using data from the first national survey of medical oncologists' perspectives on precision medicine (N = 1281), we approached our analyses in two phases. Bivariate analyses initially evaluated associations between barriers to involving patients/families in deciding to use NGS and provider- and organizational-level characteristics. Modified Poisson regressions then examined associations between patient/family barriers and NGS use. RESULTS: Approximately 59 % of oncologists reported at least one barrier to involving patients/families in decision-making regarding NGS use. Those reporting patient/family barriers tended to have fewer genomic resources at their practices, to be in rural or suburban areas, and to have a higher proportion of Medicaid patients. However, these barriers were not associated with NGS use. CONCLUSIONS: Oncologists encounter barriers to involving patients/families in NGS testing decisions. Organizational barriers may also potentially play a role in testing decisions. PRACTICE IMPLICATIONS: To foster patient-centered care, strategies to support patient involvement in genomic testing decisions are needed, particularly among practices in low-resource settings.

Racial and ethnic differences in risk of second primary cancers among prostate cancer survivors.

PURPOSE: Previous studies have shown an overall decreased risk of second cancers among prostate cancer survivors, but this has not been comprehensively examined by race/ethnicity. We conducted a retrospective cohort study of 716,319 one-year survivors of prostate cancer diagnosed at ages 35-84 during 2000-2015 as reported to 17 US Surveillance, Epidemiology and End Results (SEER) registries. METHODS: We estimated standardized incidence ratios (SIRs) for second primary non-prostate malignancies by race/ethnicity (non-Latino white, Black, Asian/Pacific Islander [API] and Latino), by Gleason, and by time since prostate cancer diagnosis. Poisson regression models were used to test heterogeneity between groups with the expected number as the offset. RESULTS: 60,707 second primary malignancies were observed. SIRs for all second cancers combined varied significantly by race/ethnicity: SIRwhite: 0.88 (95% confidence interval: 0.87-0.89), SIRLatino: 0.92 (0.89-0.95), SIRBlack: 0.97 (0.95-0.99), and SIRAPI: 1.05 (1.01-1.09) (p-heterogeneity < 0.001). SIRs for all cancers combined were higher among survivors of higher vs. lower Gleason prostate cancers irrespective of race/ethnicity. We observed significant heterogeneity by race/ethnicity in SIRs for 9 of 14 second cancer types investigated including lung, bladder, kidney, and liver. CONCLUSIONS: Our results confirm that most prostate cancer survivors have lower risks of second cancers than expected, but the magnitude varied by race/ethnicity. Exceptionally, API men had small but significantly increased risk. Further research to understand drivers of the observed race/ethnicity heterogeneity is warranted.

The Prototypes of Tobacco Users Scale (POTUS) for Cigarette Smoking and E-Cigarette Use: Development and Validation.

Endorsing prototypes of cigarette smokers predicts cigarette smoking, but less is known about prototypes of users of other tobacco products. Our study sought to establish the reliability and validity of a measure of prototypes of smokers and e-cigarette users. Participants were from a national survey of smokers and non-smokers (n = 1414), a randomized clinical trial (RCT) of adult smokers (n = 2149), and adolescent children of adults in the trial (n = 112). The Prototypes of Tobacco Users Scale (POTUS) has four positive adjectives (cool, sexy, smart, and healthy) and four negative adjectives (disgusting, unattractive, immature, and inconsiderate) describing cigarette smokers and e-cigarette users. Confirmatory factor analyses identified a two-factor solution. The POTUS demonstrated strong internal consistency reliability in all three samples (median α = 0.85) and good test-retest reliability among adults in the RCT (median r = 0.61, 1-4 weeks follow-up). In the RCT, smokers more often agreed with negative prototypes for smokers than for e-cigarette users (mean = 2.03 vs. 1.67, p < 0.05); negative prototypes at baseline were also associated with more forgoing of cigarettes and making a quit attempt at the end of the trial (Week 4 follow-up). The POTUS may be useful to public health researchers seeking to design interventions that reduce tobacco initiation or cessation through the manipulation of tobacco user prototypes.

Fatal prostate cancer incidence trends in the United States and England by race, stage, and treatment.

BACKGROUND: Differential uptake of prostate-specific antigen testing in the US and UK has been linked to between-country differences for prostate cancer incidence. We examined stage-specific fatal prostate cancer incidence trends in the US and England, by treatment and race/ethnicity. METHODS: Using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program and Public Health England's National Cancer Registration and Analysis Service, we identified prostate cancer patients diagnosed between 1995 and 2005, aged 45-84 years. Fatal prostate cancer was defined as death attributed to the disease within 10 years of diagnosis. We used age-period-cohort models to assess trends in fatal prostate cancer incidence. RESULTS: Fatal prostate cancer incidence declined in the US by -7.5% each year and increased in England by 7.7% annually. These trends were primarily driven by locoregional disease in the US and distant disease in England. Black men in both countries had twofold to threefold higher fatal prostate cancer incidence rates, when compared with their white counterparts; however, receipt of radical prostatectomy lessened this disparity. CONCLUSIONS: We report a significant increasing rate of fatal prostate cancer incidence among English men. The black-white racial disparity appears pervasive but is attenuated among those who received radical prostatectomy in the US.

Overall and abdominal obesity and prostate cancer risk in a West African population: An analysis of the Ghana Prostate Study.

Obesity has been associated with an increased risk of advanced prostate cancer. However, most studies have been conducted among North American and European populations. Prostate cancer mortality appears elevated in West Africa, yet risk factors for prostate cancer in this region are unknown. We thus examined the relationship between obesity and prostate cancer using a case-control study conducted in Accra, Ghana in 2004 to 2012. Cases and controls were drawn from a population-based sample of 1037 men screened for prostate cancer, yielding 73 cases and 964 controls. An additional 493 incident cases were recruited from the Korle-Bu Teaching Hospital. Anthropometric measurements were taken at enrollment. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR) and prostate cancer, adjusting for potential confounders. The mean BMI was 25.1 kg/m2 for cases and 24.3 kg/m2 for controls. After adjustment, men with BMI ≥ 30 kg/m2 had an increased risk of prostate cancer relative to men with BMI < 25 kg/m2 (OR 1.86, 95% CI 1.11-3.13). Elevated WC (OR 1.76, 95% CI 1.24-2.51) and WHR (OR 1.46, 95% CI 0.99-2.16) were also associated with prostate cancer. Associations were not modified by smoking status and were evident for low- and high-grade disease. These findings indicate that overall and abdominal obesity are positively associated with prostate cancer among men in Ghana, implicating obesity as a potentially modifiable risk factor for prostate cancer in this region.

Image analysis with deep learning to predict breast cancer grade, ER status, histologic subtype, and intrinsic subtype.

RNA-based, multi-gene molecular assays are available and widely used for patients with ER-positive/HER2-negative breast cancers. However, RNA-based genomic tests can be costly and are not available in many countries. Methods for inferring molecular subtype from histologic images may identify patients most likely to benefit from further genomic testing. To identify patients who could benefit from molecular testing based on H&E stained histologic images, we developed an image analysis approach using deep learning. A training set of 571 breast tumors was used to create image-based classifiers for tumor grade, ER status, PAM50 intrinsic subtype, histologic subtype, and risk of recurrence score (ROR-PT). The resulting classifiers were applied to an independent test set (n = 288), and accuracy, sensitivity, and specificity of each was assessed on the test set. Histologic image analysis with deep learning distinguished low-intermediate vs. high tumor grade (82% accuracy), ER status (84% accuracy), Basal-like vs. non-Basal-like (77% accuracy), Ductal vs. Lobular (94% accuracy), and high vs. low-medium ROR-PT score (75% accuracy). Sampling considerations in the training set minimized bias in the test set. Incorrect classification of ER status was significantly more common for Luminal B tumors. These data provide proof of principle that molecular marker status, including a critical clinical biomarker (i.e., ER status), can be predicted with accuracy >75% based on H&E features. Image-based methods could be promising for identifying patients with a greater need for further genomic testing, or in place of classically scored variables typically accomplished using human-based scoring.

TP53 protein levels, RNA-based pathway assessment, and race among invasive breast cancer cases.

Mutations in tumor suppressor TP53 have been inconsistently linked to breast cancer risk factors and survival. Immunohistochemistry (IHC) staining, a primary clinical means of TP53 mutation determination, only detects mutations that facilitate protein accumulation (e.g., missense mutations). RNA-based pathway methods capture functional status and may aid in understanding the role of TP53 function in racial disparities of breast cancer. TP53 status was assessed among invasive breast cancer cases from the Carolina Breast Cancer Study (CBCS) (2008-2013) using IHC and an established RNA-based TP53 signature (CBCS and The Cancer Genome Atlas (TCGA)). Frequency of TP53 status (IHC, RNA-based) was estimated in association with tumor characteristics, PAM50 intrinsic subtype, age, and race using relative frequency differences (RFDs) and 95% confidence intervals (95% CI) as the measure of association. Approximately 60% of basal-like tumors were TP53 protein positive (IHC), while nearly 100% were TP53 mutant-like (RNA). Luminal A tumors had low frequency of TP53 positivity (IHC: 7.9%) and mutant-like status (RNA: 1.7%). Mutant-like TP53 (RNA) was strongly associated with age ≤50 years, high tumor grade, advanced stage of disease, large tumor size, and basal-like and HER2 intrinsic subtypes. Black race was strongly associated with TP53 mutant-like status (RNA) (RFD: 24.8%, 95% CI: 20.5, 29.0) even after adjusting for age, grade, stage (RFD: 11.3%; 95% CI: 7.6, 15.0). Associations were attenuated and non-significant when measured by IHC. IHC-based TP53 status is an insensitive measurement of TP53 functional status. RNA-based methods suggest a role for TP53 in tumor prognostic features and racial disparities.

Prediagnostic Smoking Is Associated with Binary and Quantitative Measures of ER Protein and ESR1 mRNA Expression in Breast Tumors.

Background: Smoking is a possible risk factor for breast cancer and has been linked to increased risk of estrogen receptor-positive (ER+) disease in some epidemiologic studies. It is unknown whether smoking has quantitative effects on ER expression.Methods: We examined relationships between smoking and ER expression from tumors of 1,888 women diagnosed with invasive breast cancer from a population-based study in North Carolina. ER expression was characterized using binary (±) and continuous measures for ER protein, ESR1 mRNA, and a multigene luminal score (LS) that serves as a measure of estrogen signaling in breast tumors. We used logistic and linear regression models to estimate temporal and dose-dependent associations between smoking and ER measures.Results: The odds of ER+, ESR1+, and LS+ tumors among current smokers (at the time of diagnosis), those who smoked 20 or more years, and those who smoked within 5 years of diagnosis were nearly double those of nonsmokers. Quantitative levels of ESR1 were highest among current smokers compared with never smokers overall [mean (log2) = 9.2 vs. 8.7, P < 0.05] and among ER+ cases; however, we did not observe associations between smoking measures and continuous ER protein expression.Conclusions: In relationship to breast cancer diagnosis, recent smoking was associated with higher odds of the ER+, ESR1+, and LS+ subtype. Current smoking was associated with elevated ESR1 mRNA levels and an elevated LS, but not with altered ER protein.Impact: A multigene LS and single-gene ESR1 mRNA may capture tumor changes associated with smoking. Cancer Epidemiol Biomarkers Prev; 27(1); 67-74. ©2017 AACR.